Tumor-associated macrophages(TAMs)are emerging as targets for tumor therapy because of their primary role in promoting tumor progression.Several studies have been conducted to target TAMs by reducing their infiltratio...Tumor-associated macrophages(TAMs)are emerging as targets for tumor therapy because of their primary role in promoting tumor progression.Several studies have been conducted to target TAMs by reducing their infiltration,depleting their numbers,and reversing their phenotypes to suppress tumor progression,leading to the development of drugs in preclinical and clinical trials.However,the heterogeneous characteristics of TAMs,including their ontogenetic and functional heterogeneity,limit their targeting.Therefore,in-depth exploration of the heterogeneity of TAMs,combined with immune checkpoint therapy or other therapeutic modalities could improve the efficiency of tumor treatment.This review focuses on the heterogeneous ontogeny and function of TAMs,as well as the current development of tumor therapies targeting TAMs and combination strategies.展开更多
Many digestive system malignant tumors are characterized by high incidence and mortality rate.Increasing evidence has revealed that the tumor microenvironment(TME)is involved in cancer initiation and tumor progression...Many digestive system malignant tumors are characterized by high incidence and mortality rate.Increasing evidence has revealed that the tumor microenvironment(TME)is involved in cancer initiation and tumor progression.Tumor-associated macrophages(TAMs)are a predominant constituent of the TME,and participate in the regulation of various biological behaviors and influence the prognosis of digestive system cancer.TAMs can be mainly classified into the antitumor M1 phenotype and protumor M2 phenotype.The latter especially are crucial drivers of tumor invasion,growth,angiogenesis,metastasis,immunosuppression,and resistance to therapy.TAMs are of importance in the occurrence,development,diagnosis,prognosis,and treatment of common digestive system malignant tumors.In this review,we summarize the role of TAMs in common digestive system malignant tumors,including esophageal,gastric,colorectal,pancreatic and liver cancers.How TAMs promote the development of tumors,and how they act as potential therapeutic targets and their clinical applications are also described.展开更多
BACKGROUND Solid pseudopapillary tumor(SPT)is a rare pancreatic tumor.Considering its malignant behaviors,SPT has been classified as a low-grade malignant tumor.Indeed,only 9.2%of all SPT patients are initially diagno...BACKGROUND Solid pseudopapillary tumor(SPT)is a rare pancreatic tumor.Considering its malignant behaviors,SPT has been classified as a low-grade malignant tumor.Indeed,only 9.2%of all SPT patients are initially diagnosed as malignant with invasion or metastasis.Thus,one of the challenges in managing SPT patients is predicting malignant behavior.AIM To investigate the malignant behavior and tumor-associated macrophage(TAM)infiltration between different histopathologic features of SPT patients.METHODS Twenty-five formalin-fixed paraffin-embedded tissue samples from 22 patients pathologically diagnosed with an SPT between 2009 and 2019 at West China Hospital were included in this retrospective study.Integrity of the capsule and growth pattern of the tumor cells was assessed microscopically in hematoxylineosin(HE)-stained sections.Based on the histopathological features,the SPT patients were divided into two groups:capsule or invasion.Clinical features,malignant behavior,and TAM infiltration were compared between the two groups.RESULTS Among the 22 SPT patients,11 were identified for each group,having either a capsule or invasion histopathologic feature.Malignant behavior was more frequent in the invasion group,including 2 patients who had peripheral organ invasion,3 with liver metastasis,and 1 with both lymph node and spleen metastases(P=0.045).Ki-67 index of more than 3%was also more frequent in the invasion group(P=0.045).Immunohistochemical analysis showed that the invasion group had a significant increase of CD68-positive TAMs in intratumor and peritumor sites in comparison with the capsule group(all P<0.0001).Similarly,CD163-positive M2-like macrophages were also markedly increased in the intratumor and peritumor sites in the invasion group(all P<0.0001).At the liver metastasis site,both intratumor and peritumor tissues showed relatively high-level CD68-positive TAMs and CD163-positive M2-like macrophages infiltration.However,the differences between the intratumor,peritumor and normal hepatic tissues did not reach statistical significance(all P>0.05).CONCLUSION SPT patients with invasion evident under microscope were more likely to exhibit malignant behavior and TAM infiltration,especially M2-like macrophages.This finding can help in future investigations of the underlying mechanism of TAM-mediated SPT malignant behavior.展开更多
Objective The aim of this study was to explore the effects of 2-hexyl-4-pentylenic acid(HPTA)in combination with radiotherapy(RT)on distant unirradiated breast tumors.Methods Using a rat model of chemical carcinogen(7...Objective The aim of this study was to explore the effects of 2-hexyl-4-pentylenic acid(HPTA)in combination with radiotherapy(RT)on distant unirradiated breast tumors.Methods Using a rat model of chemical carcinogen(7,12-dimethylbenz[a]anthracene,DMBA)-induced breast cancer,tumor volume was monitored and treatment response was evaluated by performing HE staining,immunohistochemistry,immunofluorescence,q RT-PCR,and western blot analyses.Results The results demonstrated that HPTA in combination with RT significantly delayed the growth of distant,unirradiated breast tumors.The mechanism of action included tumor-associated macrophage(TAM)infiltration into distant tumor tissues,M1 polarization,and inhibition of tumor angiogenesis by IFN-γ.Conclusion The results suggest that the combination of HPTA with RT has an abscopal effect on distant tumors via M1-polarized TAMs,and HPTA may be considered as a new therapeutic for amplifying the efficacy of local RT for non-targeted breast tumors.展开更多
Pancreatic cancer is a kind of highly aggressive malignant tumor of the digestive system.The treatment of local tumors is mainly surgical resection,but the indications are too harsh.For advanced pancreatic cancer,chem...Pancreatic cancer is a kind of highly aggressive malignant tumor of the digestive system.The treatment of local tumors is mainly surgical resection,but the indications are too harsh.For advanced pancreatic cancer,chemotherapy is the standard treatment,but patients have severe side effects and develop drug resistance.Tumor-associated macrophages in the tumor microenvironment of pancreatic cancer are the most abundant immune cells and play a very important role in tumor development and chemoresistance.Antitumor-associated macrophage therapy has shown some therapeutic potential.Therefore,this article reviews the mechanism of tumor-associated macrophages in pancreatic cancer and the progress of tumor-associated macrophage targeted therapy.展开更多
Objective: Recent studies have shown that tumor-associated macrophages(TAMs) play an important role in cancer invasion and metastasis. Our previous studies have reported that TAMs promote the invasion and metastasis o...Objective: Recent studies have shown that tumor-associated macrophages(TAMs) play an important role in cancer invasion and metastasis. Our previous studies have reported that TAMs promote the invasion and metastasis of gastric cancer(GC) cells through the Kindlin-2 pathway. However, the mechanism needs to be clarified.Methods: THP-1 monocytes were induced by PMA/interleukin(IL)-4/IL-13 to establish an efficient TAM model in vitro and M2 macrophages were isolated via flow cytometry. A dual luciferase reporter system and chromatin immunoprecipitation(Ch IP) assay were used to investigate the mechanism of transforming growth factor β2(TGFβ2) regulating Kindlin-2 expression. Immunohistochemistry was used to study the relationships among TAM infiltration in human GC tissues, Kindlin-2 protein expression, clinicopathological parameters and prognosis in human GC tissues. A nude mouse oncogenesis model was used to verify the invasion and metastasis mechanisms in vivo.Results: We found that Kindlin-2 expression was upregulated at both m RNA and protein levels in GC cells cocultured with TAMs, associated with higher invasion rate. Kindlin-2 knockdown reduced the invasion rate of GC cells under coculture condition. TGFβ2 secreted by TAMs regulated the expression of Kindlin-2 through the transcription factor NF-кB. TAMs thus participated in the progression of GC through the TGFβ2/NF-κB/Kindlin-2 axis. Kindlin-2 expression and TAM infiltration were significantly positively correlated with TNM stage, and patients with high Kindlin-2 expression had significantly poorer overall survival than patients with low Kindlin-2 expression. Furthermore, Kindlin-2 promoted the invasion of GC cells in vivo.Conclusions: This study elucidates the mechanism of TAMs participating in GC cell invasion and metastasis through the TGFβ2/NF-κB/Kindlin-2 axis, providing a possibility for new treatment options and approaches.展开更多
AIM To study the role of semaphorin 4 D(Sema4 D) expression promoted by tumor-associated macrophages(TAMs) in gastric carcinoma cells and its clinical significance in the invasion and metastasis of gastric carcinoma.M...AIM To study the role of semaphorin 4 D(Sema4 D) expression promoted by tumor-associated macrophages(TAMs) in gastric carcinoma cells and its clinical significance in the invasion and metastasis of gastric carcinoma.METHODS CD68 and Sema4 D expression was analyzed in gastric carcinoma and adjacent normal tissues from 290 patients using the immunohistochemical streptavidinperoxidase method, and their relationships with clinicopathological features were evaluated. Human M2 macrophages were induced in vitro and co-cultured in non-contact with gastric carcinoma SGC-7901 cells. Changes in the secretory Sema4 D level in the SGC-7901 cell supernatant were measured using an enzymelinked immunosorbent assay. The effects of TAMs on SGC-7901 cell invasion and migration were assessed with invasion and migration assays, respectively.RESULTS CD68 and Sema4 D protein expression was significantly higher in gastric carcinoma tissues than in adjacent normal tissues(71.7% vs 33.8% and 74.5% vs 42.8%, respectively; P < 0.01). CD68 and Sema4 D protein expression was significantly associated with histological differentiation, TNM stage, and lymph node metastasis(P < 0.05), and their expression levels were positively correlated with one another(r = 0.467, P < 0.01). In the in vitro experiment, secretory Sema4 D protein expression was significantly increased in the supernatant of SGC-7901 cells co-cultured with TAMs compared with the blank control(1224.13 ± 29.43 vs 637.15 ± 33.84, P < 0.01). Cell invasion and metastasis were enhanced in the Transwell invasion and migration assays(P < 0.01).CONCLUSION TAMs promote the invasion and metastasis of gastric carcinoma cells possibly through upregulated secretory Sema4 D protein expression. Combined detection of TAM markers, CD68 and Sema4 D, in gastric carcinoma tissue shows potential to predict the trend of gastric carcinoma progression.展开更多
Background:Inflammation is often linked with the progress and poor outcome of lung cancer.The understanding of the relationship between tumor-associated macrophages(TAMs) and lung cancer cells involves in the underlyi...Background:Inflammation is often linked with the progress and poor outcome of lung cancer.The understanding of the relationship between tumor-associated macrophages(TAMs) and lung cancer cells involves in the underlying mechanism of inflammatory cytokine production.Toll-like receptors(TLRs) are engaged in promoting the production of pro-inflammatory cytokines and play an important role in tumor immunology.Methods:To investigate the mechanisms by which TAMs influence the production of pro-inflammatory cytokines in lung cancer cells,we established an in vitro coculture system using TAMs and human nonsmall cell lung cancer(NSCLC) cell line SPC-A1.Levels of interleukin(IL)-1β,IL-6 and IL-8 in SPC-A1 were evaluated by RT-PCR and cytometric bead array assay after being cocultured with TAMs.Expression changes of TLRs and TLRs signaling pathway proteins in SPC-A1 were further confirmed by RT-PCR and western blot.The level changes of IL-1β,IL-6 and IL-8 in SPC-A1 were also detected after the stimulation of TLRs agonists.Results:We found that the phenotype markers of TAMs were highly expressed after stimulating human monocyte cell line THP-1 by phorbol-12-myristate-13-acetate(PMA).Higher mRNA and supernate secretion levels of IL-1β,IL-6 and IL-8 were detected in SPC-A1 after being cocultured with TAMs.We also found that TLR1,TLR6 and TLR7 were up-regulated in SPC-A1 in the coculture system with TAMs.Meanwhile,TLRs signaling pathway proteins were also significantly activated.Moreover,pre-treatment with agonist ligands for TLR1,TLR6 and TLR7 could dramatically promote inductions of IL-1β,IL-6 and IL-8.Conclusions:These findings demonstrated that TAMs may enhance IL-1β,IL-6 and IL-8 expressions via TLRs signaling pathway.We conclude that TAMs contribute to maintain the inflammation microenvironment and ultimately promote the development and progression of lung cancer.展开更多
Tumor invasion and metastasis is the primary cause of death in patients with malignant tumors.Tumor-associated macrophages are macrophages that infiltrate the tumor tissue,and are the most frequent immune cells in the...Tumor invasion and metastasis is the primary cause of death in patients with malignant tumors.Tumor-associated macrophages are macrophages that infiltrate the tumor tissue,and are the most frequent immune cells in the tumor microenvironment.The macrophages could secrete a variety of cytokines and can recognize,identify and clear the tumor cells.As the tumor develops,it plays a vital role in the growth,invasion and metastasis of the cancer.However,the underline mechanisms of how the tumor-associated macrophages promoting tumor metastasis is still not fully understood.Present studies demonstrated that macrophage-related exosomes might play an essential role in tumor metastasis.Exosomes may provide potential targets for the prevention and treatment of macrophage-related tumor metastasis.展开更多
The main challenges in the use of immune checkpoint inhibitors(ICIs)are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+T cells.Transforming the tumor ...The main challenges in the use of immune checkpoint inhibitors(ICIs)are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+T cells.Transforming the tumor microenvironment(TME)from“cold”to“hot”and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer treatment.We found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+mouse models.Using single-cell RNA sequencing,we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion,restoring T-cell function and promoting a favorable immunotherapy response.Mechanistically,we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling,thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine production.As a result,APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment,thus improving tumor immunosuppression and further enhancing antitumor T-cell immunity.Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86,p-NF-κB p65 and NLRP3 levels,accompanied by lower CD206 expression on macrophages.Collectively,these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.展开更多
BACKGROUND Colorectal cancer(CRC)is a prevalent global malignancy with complex prognostic factors.Tumor-associated macrophages(TAMs)have shown paradoxical associations with CRC survival,particularly concerning the M2 ...BACKGROUND Colorectal cancer(CRC)is a prevalent global malignancy with complex prognostic factors.Tumor-associated macrophages(TAMs)have shown paradoxical associations with CRC survival,particularly concerning the M2 subset.AIM We aimed to establish a simplified protocol for quantifying M2-like TAMs and explore their correlation with clinicopathological factors.METHODS A cross-sectional study included histopathological assessment of paraffinembedded tissue blocks obtained from 43 CRC patients.Using CD68 and CD163 immunohistochemistry,we quantified TAMs in tumor stroma and front,focusing on M2 proportion.Demographic,histopathological,and clinical parameters were collected.RESULTS TAM density was significantly higher at the tumor front,with the M2 proportion three times greater in both zones.The tumor front had a higher M2 proportion,which correlated significantly with advanced tumor stage(P=0.04),pathological nodal involvement(P=0.04),and lymphovascular invasion(LVI,P=0.01).However,no significant association was found between the M2 proportion in the tumor stroma and clinicopathological factors.CONCLUSION Our study introduces a simplified protocol for quantifying M2-like TAMs in CRC tissue samples.We demonstrated a significant correlation between an increased M2 proportion at the tumor front and advanced tumor stage,nodal involvement,and LVI.This suggests that M2-like TAMs might serve as potential indicators of disease progression in CRC,warranting further investigation and potential clinical application.展开更多
Objective:Tumor-associated macrophages(TAMs)of the M2 phenotype are frequently associated with cancer progression.Invasive cancer cells undergoing epithelial-mesenchymal transition(EMT)have a selective advantage as TA...Objective:Tumor-associated macrophages(TAMs)of the M2 phenotype are frequently associated with cancer progression.Invasive cancer cells undergoing epithelial-mesenchymal transition(EMT)have a selective advantage as TAM activators.Cyclin D1b is a highly oncogenic splice variant of cyclin D1.We previously reported that cyclin D1b enhances the invasiveness of breast cancer cells by inducing EMT.However,the role of cyclin D1b in inducing macrophage differentiation toward tumor-associated macrophage-like cells remains unknown.This study aimed to explore the relationship between breast cancer cells overexpressing cyclin Dlb and TAMs.Methods:Mouse breast cancer 4T1 cells were transfected with cyclin D1b variant and co-cultured with macrophage cells in a Transwell coculture system.The expression of characteristic cytokines in differentiated macrophages was detected using qRT-PCR,ELISA and zymography assay.Tumor-associated macrophage distribution in a transplanted tumor was detected by immunofluorescence staining.The proliferation and migration ability of breast cancer cells was detected using the cell counting kit-8(CCK-8)assay,wound healing assay,Transwell invasion assay,and lung metastasis assay.Expression levels of mRNAs were detected by qRT-PCR.Protein expression levels were detected by Western blotting.The integrated analyses of The Cancer Genome Atlas(TCGA)datasets and bioinformatics methods were adopted to discover gene expression,gene coexpression,and overall survival in patients with breast cancer.Results:After co-culture with breast cancer cells overexpressing cyclin D1b,RAW264.7 macrophages were differentiated into an M2 phenotype.Moreover,differentiated M2-like macrophages promoted the proliferation and migration of breast cancer cells in turn.Notably,these macrophages facilitated the migration of breast cancer cells in vivo.Further investigations indicated that differentiated M2-like macrophages induced EMT of breast cancer cells accompanied with upregulation of TGF-β1 and integrinβ3 expression.Conclusion:Breast cancer cells transfected with cyclin D1b can induce the differentiation of macrophages into a tumor-associated macrophage-like phenotype,which promotes tumor metastasis in vitro and in vivo.展开更多
Polarization of tumor associated macrophages(TAMs)has been a promising therapeutic paradigm for tumor.However,how to achieve precise regulation of TAMs and high efficiency of tumor immunotherapy is still a huge challe...Polarization of tumor associated macrophages(TAMs)has been a promising therapeutic paradigm for tumor.However,how to achieve precise regulation of TAMs and high efficiency of tumor immunotherapy is still a huge challenge.Here,we report dicarboxy fullerene modified with mannose(DCFM)as an immunomodulator to selectively polarize TAMs and prominently boost anti-tumor immunity.The dicarboxy fullerene molecule was synthesized through the Prato reaction and further covalently bonded with mannose,obtaining the DCFM with well-defined structure.Due to the exist of mannose in DCFM,it could accurately recognize mannose receptor in TAMs.Our cellular experiment results showed that mannose modification could notably promote the uptake of DCFM by the immunosuppressive M2-type macrophages that effectively reprogrammed M2-type macrophages into anti-tumor M1-type macrophages,leading to enhance the phagocytosis of tumor cells by macrophages and inhibiting tumor cells migration.Subsequently,we observed that DCFM could significantly distribute into tumor tissues by in vivo fluorescence imaging.Importantly,DCFM exhibited a superior anti-tumor efficiency in the subcutaneous colorectal tumor model.In addition,it showed that DCFM precisely polarized TAMs into M1-type macrophages and actively increased the infiltration of cytotoxic T lymphocytes(CTLs),inducing profound tumor growth inhibition.展开更多
Highly immunosuppressive tumor microenvironment containing various protumoral immune cells accelerates malignant transformation and treatment resistance.In particular,tumor-associated macrophages(TAMs),as the predomin...Highly immunosuppressive tumor microenvironment containing various protumoral immune cells accelerates malignant transformation and treatment resistance.In particular,tumor-associated macrophages(TAMs),as the predominant infiltrated immune cells in a tumor,play a pivotal role in regulating the immunosuppressive tumor microenvironment.As a potential therapeutic strategy to counteract TAMs,here we explore an exosome-guided in situ direct reprogramming of tumor-supportive M2-polarized TAMs into tumor-attacking M1-type macrophages.Exosomes derived from M1-type macrophages(M1-Exo)promote a phenotypic switch from anti-inflammatory M2-like TAMs toward pro-inflammatory M1-type macrophages with high conversion efficiency.Reprogrammed M1 macrophages possessing protein-expression profiles similar to those of classically activated M1 macrophages display significantly increased phagocytic function and robust cross-presentation ability,potentiating antitumor immunity surrounding the tumor.Strikingly,these M1-Exo also lead to the conversion of human patient-derived TAMs into M1-like macrophages that highly express MHC class II,offering the clinical potential of autologous and allogeneic exosome-guided direct TAM reprogramming for arming macrophages to join the fight against cancer.展开更多
Macrophages have a leading position in the tumor microenvironment(TME)which paves the way to carcinogenesis.Initially,monocytes and macrophages are recruited to the sites where the tumor develops.Under the guidance of...Macrophages have a leading position in the tumor microenvironment(TME)which paves the way to carcinogenesis.Initially,monocytes and macrophages are recruited to the sites where the tumor develops.Under the guidance of different microenvironmental signals,macrophages would polarize into two functional phenotypes,named as classically activated macrophages(M1)and alternatively activated macrophages(M2).Contrary to the anti-tumor effect of M1,M2 exerts anti-inflammatory and tumorigenic characters.In progressive tumor,M2 tumor-associated macrophages(TAMs)are in the majority,being vital regulators reacting upon TME.This review elaborates on the role of TAMs in tumor progression.Furthermore,prospective macrophage-focused therapeutic strategies,including drugs not only in clinical trials but also at primary research stages,are summarized followed by a discussion about their clinical application values.Nanoparticulate systems with efficient drug delivery and improved antitumor effect are also summed up in this article.展开更多
Multidimensional analyses have demonstrated the presence of a unique tumor microenvironment(TME)in liver cancer.Tumor-associated macrophages(TAMs)are among the most abundant immune cells infiltrating the TME and are p...Multidimensional analyses have demonstrated the presence of a unique tumor microenvironment(TME)in liver cancer.Tumor-associated macrophages(TAMs)are among the most abundant immune cells infiltrating the TME and are present at all stages of liver cancer progression,and targeting TAMs has become one of the most favored immunotherapy strategies.In addition,macrophages and liver cancer cells have distinct origins.At the early stage of liver cancer,macrophages can provide a niche for the maintenance of liver cancer stem cells.In contrast,cancer stem cells(CSCs)or poorly differentiated tumor cells are key factors modulating macrophage activation.In the present review,we first propose the origin connection between precursor macrophages and liver cancer cells.Macrophages undergo dynamic phenotypic transition during carcinogenesis.In this course of such transition,it is critical to determine the appropriate timing for therapy and block specific markers to suppress protumoral TAMs.The present review provides a more detailed discussion of transition trends of such surface markers than previous reviews.Complex crosstalk occurs between TAMs and liver cancer cells.TAMs play indispensable roles in tumor progression,angiogenesis,and autophagy due to their heterogeneity and robust plasticity.In addition,macrophages in the TME interact with other immune cells by directing cell-to-cell contact or secreting various effector molecules.Similarly,tumor cells combined with other immune cells can drive macrophage recruitment and polarization.Despite the latest achievements and the advancements in treatment strategies following TAMs studies,comprehensive discussions on the communication between macrophages and cancer cells or immune cells in liver cancer are currently lacking.In this review,we discussed the interactions between TAMs and liver cancer cells(from cell origin to maturation),the latest therapeutic strategies(including chimeric antigen receptor macrophages),and critical clinical trials for hepatocellular carcinoma(HCC)and intrahepatic cholangiocar-cinoma(iCCA)to provide a rationale for further clinical investigation of TAMs as a potential target for treating patients with liver cancer.展开更多
Tumor-associated macrophages(TAMs)are an essential proportion of tumor-infiltrating immune cells in the tumor microenvironment(TME)and have immunosuppressive functions.The high plasticity and corresponding phenotypic ...Tumor-associated macrophages(TAMs)are an essential proportion of tumor-infiltrating immune cells in the tumor microenvironment(TME)and have immunosuppressive functions.The high plasticity and corresponding phenotypic transformation of TAMs facilitate oncogenesis and progression,and suppress antineoplastic responses.Due to the uncontrolled proliferation of tumor cells,metabolism homeostasis is regulated,leading to a series of alterations in the metabolite profiles in the TME,which have a commensurate influence on immune cells.Metabolic reprogramming of the TME has a profound impact on the polarization and function of TAMs,and can alter their metabolic profiles.TAMs undergo a series of metabolic reprogramming processes,involving glucose,lipid,and amino acid metabolism,and other metabolic pathways,which terminally promote the development of the immunosuppressive phenotype.TAMs express a pro-tumor phenotype by increasing glycolysis,fatty acid oxidation,cholesterol efflux,and arginine,tryptophan,glutamate,and glutamine metabolism.Previous studies on the metabolism of TAMs demonstrated that metabolic reprogramming has intimate crosstalk with anti-tumor or pro-tumor phenotypes and is crucial for the function of TAMs themselves.Targeting metabolism-related pathways is emerging as a promising therapeutic modality because of the massive metabolic remodeling that occurs in malignant cells and TAMs.Evidence reveals that the efficacy of immune checkpoint inhibitors is improved when combined with therapeutic strategies targeting metabolism-related pathways.In-depth research on metabolic reprogramming and potential therapeutic targets provides more options for anti-tumor treatment and creates new directions for the development of new immunotherapy methods.In this review,we elucidate the metabolic reprogramming of TAMs and explore how they sustain immunosuppressive phenotypes to provide a perspective for potential metabolic therapies.展开更多
The immunosuppressive tumor microenvironment(TME)is crucial in the occurrence of tumorigenesis,metastasis,and drug resistance.Among all stromal cells,tumor-associated macrophages(TAMs)are recognized as vital component...The immunosuppressive tumor microenvironment(TME)is crucial in the occurrence of tumorigenesis,metastasis,and drug resistance.Among all stromal cells,tumor-associated macrophages(TAMs)are recognized as vital components causing the TME to be favorable for cancer cells and are also main targets in cancer immunotherapy.To date,nanoparticle(NP)-based drug delivery systems,as new technology platforms,have exhibited considerable advantages,such as targeted drug delivery at tumor sites,enhanced drug transport efficiency,and controllable drug release profiles,which provide new approaches for cancer therapy.Regarding TAM-targeting nanoparticles,various therapeutic strategies have been developed by varying their design,namely,by blocking TAM recruitment,promoting TAM transformation,and directly diminishing existing TAMs.In the current review,we provide a brief overview of the role of TAMs in the tumor microenvironment and their functions and highlight strategies for TAM targeting.Moreover,the applications of nanoparticles in targeting TAMs to improve cancer therapeutic efficiency are summarized.展开更多
Gliomas,the most common primary tumors in the central nervous system(CNS),can be categorized into 4 grades according to the World Health Organization.The most malignant glioma type is gradeⅣ,also named glioblastoma m...Gliomas,the most common primary tumors in the central nervous system(CNS),can be categorized into 4 grades according to the World Health Organization.The most malignant glioma type is gradeⅣ,also named glioblastoma multiforme(GBM).However,the standard treatment of concurrent temozolomide(TMZ)chemotherapy and radiotherapy after maximum resection does not improve overall survival in patients with GBM.Targeting components of the CNS microenvironment represents a new strategy for improving the efficacy of glioma treatment.Most recent studies focused on T cells.However,there is a growing body of evidence that tumor-associated macrophages(TAMs)play an important role in tumor progression and can be regulated by a wide array of cytokines or chemokines.New TAM-associated immunotherapies may improve clinical outcomes by blocking tumor progression and prolonging survival.However,understanding the exact roles and possible mechanisms of TAMs in the tumor environment is necessary for developing this promising therapeutic target and identifying potential diagnostic markers for improved prognosis.This review summarizes the possible interactions between TAMs and glioma progression and discusses the potential therapeutic directions for TAM-associated immunotherapies.展开更多
Background:Interleukin-15(IL-15)is a promising immunotherapeutic agent owing to its powerful immune-activating effects.However,the clinical benefits of these treatments are limited.Crosstalk between tumor cells and im...Background:Interleukin-15(IL-15)is a promising immunotherapeutic agent owing to its powerful immune-activating effects.However,the clinical benefits of these treatments are limited.Crosstalk between tumor cells and immune cells plays an important role in immune escape and immunotherapy drug resistance.Herein,this study aimed to obtain in-depth understanding of crosstalk in the tumor microenvironment for providing potential therapeutic strategies to prevent tumor progression.Methods:T-cell killing assays and co-culture models were developed to determine the role of crosstalk between macrophages and tumor cells in breast cancer resistant to IL-15.Western blotting,histological analysis,CRISPR-Cas9 knockout,multi-parameter flow cytometry,and tumor cell-macrophage co-injection mouse models were developed to examine the mechanism by which IL-15Rα^(+)tumor-associated macrophages(TAMs)regulate breast cancer cell resistance to IL-15.Results:We found thatmacrophages contributed to the resistance of tumor cells to IL-15,and tumor cells induced macrophages to express high levels of theαsubunit of the IL-15 receptor(IL-15Rα).Further investigation showed that IL-15Rα^(+)TAMs reduced the protein levels of chemokine CX3C chemokine ligand 1(CX3CL1)in tumor cells to inhibit the recruitment of CD8^(+)T cells by releasing the IL-15/IL-15Rαcomplex(IL-15Rc).Administration of an IL-15Rc blocking peptide markedly suppressed breast tumor growth and overcame the resistance of cancer cells to anti-programmed cell death protein 1(PD-1)antibody immunotherapy.Interestingly,Granulocyte-macrophage colony-stimulating factor(GMCSF)inducedγchain(γc)expression to promote tumor cell-macrophage crosstalk,which facilitated tumor resistance to IL-15.Additionally,we observed that the non-transcriptional regulatory function of hypoxia inducible factor-1alpha(HIF-1α)was essential for IL-15Rc to regulateCX3CL1 expression in tumor cells.Conclusions:The IL-15Rc-HIF-1α-CX3CL1 signaling pathway serves as a crosstalk between macrophages and tumor cells in the tumormicroenvironment of breast cancer.Targeting this pathway may provide a potential therapeutic strategy for enhancing the efficacy of cancer immunotherapy.展开更多
基金This work was supported by the National Natural Science Foundation of China(82003018).
文摘Tumor-associated macrophages(TAMs)are emerging as targets for tumor therapy because of their primary role in promoting tumor progression.Several studies have been conducted to target TAMs by reducing their infiltration,depleting their numbers,and reversing their phenotypes to suppress tumor progression,leading to the development of drugs in preclinical and clinical trials.However,the heterogeneous characteristics of TAMs,including their ontogenetic and functional heterogeneity,limit their targeting.Therefore,in-depth exploration of the heterogeneity of TAMs,combined with immune checkpoint therapy or other therapeutic modalities could improve the efficiency of tumor treatment.This review focuses on the heterogeneous ontogeny and function of TAMs,as well as the current development of tumor therapies targeting TAMs and combination strategies.
基金Supported by National Natural Science Foundation of China,No.82272396Suzhou Medical and Health Science and Technology Innovation Project,No.SKY2022057The Youth Medical Talent of Jiangsu Province,No.QNRC2016475.
文摘Many digestive system malignant tumors are characterized by high incidence and mortality rate.Increasing evidence has revealed that the tumor microenvironment(TME)is involved in cancer initiation and tumor progression.Tumor-associated macrophages(TAMs)are a predominant constituent of the TME,and participate in the regulation of various biological behaviors and influence the prognosis of digestive system cancer.TAMs can be mainly classified into the antitumor M1 phenotype and protumor M2 phenotype.The latter especially are crucial drivers of tumor invasion,growth,angiogenesis,metastasis,immunosuppression,and resistance to therapy.TAMs are of importance in the occurrence,development,diagnosis,prognosis,and treatment of common digestive system malignant tumors.In this review,we summarize the role of TAMs in common digestive system malignant tumors,including esophageal,gastric,colorectal,pancreatic and liver cancers.How TAMs promote the development of tumors,and how they act as potential therapeutic targets and their clinical applications are also described.
基金Supported by Natural Science Foundation of China,No. 82071746Key Research and Development Projects in Sichuan Province,No. 2019YFS00431·3·5 Project for Disciplines of Excellence–Clinical Research Incubation Project,West China Hospital,Sichuan University,No. ZY2017302
文摘BACKGROUND Solid pseudopapillary tumor(SPT)is a rare pancreatic tumor.Considering its malignant behaviors,SPT has been classified as a low-grade malignant tumor.Indeed,only 9.2%of all SPT patients are initially diagnosed as malignant with invasion or metastasis.Thus,one of the challenges in managing SPT patients is predicting malignant behavior.AIM To investigate the malignant behavior and tumor-associated macrophage(TAM)infiltration between different histopathologic features of SPT patients.METHODS Twenty-five formalin-fixed paraffin-embedded tissue samples from 22 patients pathologically diagnosed with an SPT between 2009 and 2019 at West China Hospital were included in this retrospective study.Integrity of the capsule and growth pattern of the tumor cells was assessed microscopically in hematoxylineosin(HE)-stained sections.Based on the histopathological features,the SPT patients were divided into two groups:capsule or invasion.Clinical features,malignant behavior,and TAM infiltration were compared between the two groups.RESULTS Among the 22 SPT patients,11 were identified for each group,having either a capsule or invasion histopathologic feature.Malignant behavior was more frequent in the invasion group,including 2 patients who had peripheral organ invasion,3 with liver metastasis,and 1 with both lymph node and spleen metastases(P=0.045).Ki-67 index of more than 3%was also more frequent in the invasion group(P=0.045).Immunohistochemical analysis showed that the invasion group had a significant increase of CD68-positive TAMs in intratumor and peritumor sites in comparison with the capsule group(all P<0.0001).Similarly,CD163-positive M2-like macrophages were also markedly increased in the intratumor and peritumor sites in the invasion group(all P<0.0001).At the liver metastasis site,both intratumor and peritumor tissues showed relatively high-level CD68-positive TAMs and CD163-positive M2-like macrophages infiltration.However,the differences between the intratumor,peritumor and normal hepatic tissues did not reach statistical significance(all P>0.05).CONCLUSION SPT patients with invasion evident under microscope were more likely to exhibit malignant behavior and TAM infiltration,especially M2-like macrophages.This finding can help in future investigations of the underlying mechanism of TAM-mediated SPT malignant behavior.
基金supported by The National Natural Science Foundation of China 81472800Department of Science and Technology of Shandong Province 2019GSF108083Natural Science Foundation of Shandong Province ZR2020MH330。
文摘Objective The aim of this study was to explore the effects of 2-hexyl-4-pentylenic acid(HPTA)in combination with radiotherapy(RT)on distant unirradiated breast tumors.Methods Using a rat model of chemical carcinogen(7,12-dimethylbenz[a]anthracene,DMBA)-induced breast cancer,tumor volume was monitored and treatment response was evaluated by performing HE staining,immunohistochemistry,immunofluorescence,q RT-PCR,and western blot analyses.Results The results demonstrated that HPTA in combination with RT significantly delayed the growth of distant,unirradiated breast tumors.The mechanism of action included tumor-associated macrophage(TAM)infiltration into distant tumor tissues,M1 polarization,and inhibition of tumor angiogenesis by IFN-γ.Conclusion The results suggest that the combination of HPTA with RT has an abscopal effect on distant tumors via M1-polarized TAMs,and HPTA may be considered as a new therapeutic for amplifying the efficacy of local RT for non-targeted breast tumors.
基金Key R&D project of Shanxi Province(No.201903D321144)。
文摘Pancreatic cancer is a kind of highly aggressive malignant tumor of the digestive system.The treatment of local tumors is mainly surgical resection,but the indications are too harsh.For advanced pancreatic cancer,chemotherapy is the standard treatment,but patients have severe side effects and develop drug resistance.Tumor-associated macrophages in the tumor microenvironment of pancreatic cancer are the most abundant immune cells and play a very important role in tumor development and chemoresistance.Antitumor-associated macrophage therapy has shown some therapeutic potential.Therefore,this article reviews the mechanism of tumor-associated macrophages in pancreatic cancer and the progress of tumor-associated macrophage targeted therapy.
基金supported by grants from the National Natural Science Foundation of China (No. 81372291).
文摘Objective: Recent studies have shown that tumor-associated macrophages(TAMs) play an important role in cancer invasion and metastasis. Our previous studies have reported that TAMs promote the invasion and metastasis of gastric cancer(GC) cells through the Kindlin-2 pathway. However, the mechanism needs to be clarified.Methods: THP-1 monocytes were induced by PMA/interleukin(IL)-4/IL-13 to establish an efficient TAM model in vitro and M2 macrophages were isolated via flow cytometry. A dual luciferase reporter system and chromatin immunoprecipitation(Ch IP) assay were used to investigate the mechanism of transforming growth factor β2(TGFβ2) regulating Kindlin-2 expression. Immunohistochemistry was used to study the relationships among TAM infiltration in human GC tissues, Kindlin-2 protein expression, clinicopathological parameters and prognosis in human GC tissues. A nude mouse oncogenesis model was used to verify the invasion and metastasis mechanisms in vivo.Results: We found that Kindlin-2 expression was upregulated at both m RNA and protein levels in GC cells cocultured with TAMs, associated with higher invasion rate. Kindlin-2 knockdown reduced the invasion rate of GC cells under coculture condition. TGFβ2 secreted by TAMs regulated the expression of Kindlin-2 through the transcription factor NF-кB. TAMs thus participated in the progression of GC through the TGFβ2/NF-κB/Kindlin-2 axis. Kindlin-2 expression and TAM infiltration were significantly positively correlated with TNM stage, and patients with high Kindlin-2 expression had significantly poorer overall survival than patients with low Kindlin-2 expression. Furthermore, Kindlin-2 promoted the invasion of GC cells in vivo.Conclusions: This study elucidates the mechanism of TAMs participating in GC cell invasion and metastasis through the TGFβ2/NF-κB/Kindlin-2 axis, providing a possibility for new treatment options and approaches.
文摘AIM To study the role of semaphorin 4 D(Sema4 D) expression promoted by tumor-associated macrophages(TAMs) in gastric carcinoma cells and its clinical significance in the invasion and metastasis of gastric carcinoma.METHODS CD68 and Sema4 D expression was analyzed in gastric carcinoma and adjacent normal tissues from 290 patients using the immunohistochemical streptavidinperoxidase method, and their relationships with clinicopathological features were evaluated. Human M2 macrophages were induced in vitro and co-cultured in non-contact with gastric carcinoma SGC-7901 cells. Changes in the secretory Sema4 D level in the SGC-7901 cell supernatant were measured using an enzymelinked immunosorbent assay. The effects of TAMs on SGC-7901 cell invasion and migration were assessed with invasion and migration assays, respectively.RESULTS CD68 and Sema4 D protein expression was significantly higher in gastric carcinoma tissues than in adjacent normal tissues(71.7% vs 33.8% and 74.5% vs 42.8%, respectively; P < 0.01). CD68 and Sema4 D protein expression was significantly associated with histological differentiation, TNM stage, and lymph node metastasis(P < 0.05), and their expression levels were positively correlated with one another(r = 0.467, P < 0.01). In the in vitro experiment, secretory Sema4 D protein expression was significantly increased in the supernatant of SGC-7901 cells co-cultured with TAMs compared with the blank control(1224.13 ± 29.43 vs 637.15 ± 33.84, P < 0.01). Cell invasion and metastasis were enhanced in the Transwell invasion and migration assays(P < 0.01).CONCLUSION TAMs promote the invasion and metastasis of gastric carcinoma cells possibly through upregulated secretory Sema4 D protein expression. Combined detection of TAM markers, CD68 and Sema4 D, in gastric carcinoma tissue shows potential to predict the trend of gastric carcinoma progression.
基金the technical support from National Key Clinical Department of Laboratory Medicine of Jiangsu Province Hospitalsupported by National Natural Science Foundation of China(No. 81272324,81371894)+1 种基金Key Laboratory for Medicine of Jiangsu Province of China(No.XK201114)project funded by the Priority Academic Program Development ofJiangsu Higher Education Institutions
文摘Background:Inflammation is often linked with the progress and poor outcome of lung cancer.The understanding of the relationship between tumor-associated macrophages(TAMs) and lung cancer cells involves in the underlying mechanism of inflammatory cytokine production.Toll-like receptors(TLRs) are engaged in promoting the production of pro-inflammatory cytokines and play an important role in tumor immunology.Methods:To investigate the mechanisms by which TAMs influence the production of pro-inflammatory cytokines in lung cancer cells,we established an in vitro coculture system using TAMs and human nonsmall cell lung cancer(NSCLC) cell line SPC-A1.Levels of interleukin(IL)-1β,IL-6 and IL-8 in SPC-A1 were evaluated by RT-PCR and cytometric bead array assay after being cocultured with TAMs.Expression changes of TLRs and TLRs signaling pathway proteins in SPC-A1 were further confirmed by RT-PCR and western blot.The level changes of IL-1β,IL-6 and IL-8 in SPC-A1 were also detected after the stimulation of TLRs agonists.Results:We found that the phenotype markers of TAMs were highly expressed after stimulating human monocyte cell line THP-1 by phorbol-12-myristate-13-acetate(PMA).Higher mRNA and supernate secretion levels of IL-1β,IL-6 and IL-8 were detected in SPC-A1 after being cocultured with TAMs.We also found that TLR1,TLR6 and TLR7 were up-regulated in SPC-A1 in the coculture system with TAMs.Meanwhile,TLRs signaling pathway proteins were also significantly activated.Moreover,pre-treatment with agonist ligands for TLR1,TLR6 and TLR7 could dramatically promote inductions of IL-1β,IL-6 and IL-8.Conclusions:These findings demonstrated that TAMs may enhance IL-1β,IL-6 and IL-8 expressions via TLRs signaling pathway.We conclude that TAMs contribute to maintain the inflammation microenvironment and ultimately promote the development and progression of lung cancer.
文摘Tumor invasion and metastasis is the primary cause of death in patients with malignant tumors.Tumor-associated macrophages are macrophages that infiltrate the tumor tissue,and are the most frequent immune cells in the tumor microenvironment.The macrophages could secrete a variety of cytokines and can recognize,identify and clear the tumor cells.As the tumor develops,it plays a vital role in the growth,invasion and metastasis of the cancer.However,the underline mechanisms of how the tumor-associated macrophages promoting tumor metastasis is still not fully understood.Present studies demonstrated that macrophage-related exosomes might play an essential role in tumor metastasis.Exosomes may provide potential targets for the prevention and treatment of macrophage-related tumor metastasis.
基金supported by the Chinese National Natural Science Foundation Project(82073396,82303807)the Guangzhou Key Research and Development Plan(202206010141)+1 种基金the China National Postdoctoral Program for Innovative Talents(BX20230444)the China Postdoctoral Science Foundation(2023M734032).
文摘The main challenges in the use of immune checkpoint inhibitors(ICIs)are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+T cells.Transforming the tumor microenvironment(TME)from“cold”to“hot”and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer treatment.We found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+mouse models.Using single-cell RNA sequencing,we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion,restoring T-cell function and promoting a favorable immunotherapy response.Mechanistically,we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling,thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine production.As a result,APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment,thus improving tumor immunosuppression and further enhancing antitumor T-cell immunity.Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86,p-NF-κB p65 and NLRP3 levels,accompanied by lower CD206 expression on macrophages.Collectively,these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.
文摘BACKGROUND Colorectal cancer(CRC)is a prevalent global malignancy with complex prognostic factors.Tumor-associated macrophages(TAMs)have shown paradoxical associations with CRC survival,particularly concerning the M2 subset.AIM We aimed to establish a simplified protocol for quantifying M2-like TAMs and explore their correlation with clinicopathological factors.METHODS A cross-sectional study included histopathological assessment of paraffinembedded tissue blocks obtained from 43 CRC patients.Using CD68 and CD163 immunohistochemistry,we quantified TAMs in tumor stroma and front,focusing on M2 proportion.Demographic,histopathological,and clinical parameters were collected.RESULTS TAM density was significantly higher at the tumor front,with the M2 proportion three times greater in both zones.The tumor front had a higher M2 proportion,which correlated significantly with advanced tumor stage(P=0.04),pathological nodal involvement(P=0.04),and lymphovascular invasion(LVI,P=0.01).However,no significant association was found between the M2 proportion in the tumor stroma and clinicopathological factors.CONCLUSION Our study introduces a simplified protocol for quantifying M2-like TAMs in CRC tissue samples.We demonstrated a significant correlation between an increased M2 proportion at the tumor front and advanced tumor stage,nodal involvement,and LVI.This suggests that M2-like TAMs might serve as potential indicators of disease progression in CRC,warranting further investigation and potential clinical application.
基金supported by the National Natural Science Foundation of China(No.81702920,No.82174020).
文摘Objective:Tumor-associated macrophages(TAMs)of the M2 phenotype are frequently associated with cancer progression.Invasive cancer cells undergoing epithelial-mesenchymal transition(EMT)have a selective advantage as TAM activators.Cyclin D1b is a highly oncogenic splice variant of cyclin D1.We previously reported that cyclin D1b enhances the invasiveness of breast cancer cells by inducing EMT.However,the role of cyclin D1b in inducing macrophage differentiation toward tumor-associated macrophage-like cells remains unknown.This study aimed to explore the relationship between breast cancer cells overexpressing cyclin Dlb and TAMs.Methods:Mouse breast cancer 4T1 cells were transfected with cyclin D1b variant and co-cultured with macrophage cells in a Transwell coculture system.The expression of characteristic cytokines in differentiated macrophages was detected using qRT-PCR,ELISA and zymography assay.Tumor-associated macrophage distribution in a transplanted tumor was detected by immunofluorescence staining.The proliferation and migration ability of breast cancer cells was detected using the cell counting kit-8(CCK-8)assay,wound healing assay,Transwell invasion assay,and lung metastasis assay.Expression levels of mRNAs were detected by qRT-PCR.Protein expression levels were detected by Western blotting.The integrated analyses of The Cancer Genome Atlas(TCGA)datasets and bioinformatics methods were adopted to discover gene expression,gene coexpression,and overall survival in patients with breast cancer.Results:After co-culture with breast cancer cells overexpressing cyclin D1b,RAW264.7 macrophages were differentiated into an M2 phenotype.Moreover,differentiated M2-like macrophages promoted the proliferation and migration of breast cancer cells in turn.Notably,these macrophages facilitated the migration of breast cancer cells in vivo.Further investigations indicated that differentiated M2-like macrophages induced EMT of breast cancer cells accompanied with upregulation of TGF-β1 and integrinβ3 expression.Conclusion:Breast cancer cells transfected with cyclin D1b can induce the differentiation of macrophages into a tumor-associated macrophage-like phenotype,which promotes tumor metastasis in vitro and in vivo.
基金supported by the National Natural Science Foundation of China(No.92061123).M.M.Z.particularly thanks the Youth Innovation Promotion Association of CAS(No.2022036).
文摘Polarization of tumor associated macrophages(TAMs)has been a promising therapeutic paradigm for tumor.However,how to achieve precise regulation of TAMs and high efficiency of tumor immunotherapy is still a huge challenge.Here,we report dicarboxy fullerene modified with mannose(DCFM)as an immunomodulator to selectively polarize TAMs and prominently boost anti-tumor immunity.The dicarboxy fullerene molecule was synthesized through the Prato reaction and further covalently bonded with mannose,obtaining the DCFM with well-defined structure.Due to the exist of mannose in DCFM,it could accurately recognize mannose receptor in TAMs.Our cellular experiment results showed that mannose modification could notably promote the uptake of DCFM by the immunosuppressive M2-type macrophages that effectively reprogrammed M2-type macrophages into anti-tumor M1-type macrophages,leading to enhance the phagocytosis of tumor cells by macrophages and inhibiting tumor cells migration.Subsequently,we observed that DCFM could significantly distribute into tumor tissues by in vivo fluorescence imaging.Importantly,DCFM exhibited a superior anti-tumor efficiency in the subcutaneous colorectal tumor model.In addition,it showed that DCFM precisely polarized TAMs into M1-type macrophages and actively increased the infiltration of cytotoxic T lymphocytes(CTLs),inducing profound tumor growth inhibition.
基金This work was supported by the Samsung Research Funding&Incubation Center of Samsung Electronics(SRFC-MA1901-10)and the Intramural Research Program of KIST.
文摘Highly immunosuppressive tumor microenvironment containing various protumoral immune cells accelerates malignant transformation and treatment resistance.In particular,tumor-associated macrophages(TAMs),as the predominant infiltrated immune cells in a tumor,play a pivotal role in regulating the immunosuppressive tumor microenvironment.As a potential therapeutic strategy to counteract TAMs,here we explore an exosome-guided in situ direct reprogramming of tumor-supportive M2-polarized TAMs into tumor-attacking M1-type macrophages.Exosomes derived from M1-type macrophages(M1-Exo)promote a phenotypic switch from anti-inflammatory M2-like TAMs toward pro-inflammatory M1-type macrophages with high conversion efficiency.Reprogrammed M1 macrophages possessing protein-expression profiles similar to those of classically activated M1 macrophages display significantly increased phagocytic function and robust cross-presentation ability,potentiating antitumor immunity surrounding the tumor.Strikingly,these M1-Exo also lead to the conversion of human patient-derived TAMs into M1-like macrophages that highly express MHC class II,offering the clinical potential of autologous and allogeneic exosome-guided direct TAM reprogramming for arming macrophages to join the fight against cancer.
基金supported by the National Natural Science Foundation of China(Nos.81673022,81572952 and 81373346)National Key R&D Program of China(No.2017YFE0102200)
文摘Macrophages have a leading position in the tumor microenvironment(TME)which paves the way to carcinogenesis.Initially,monocytes and macrophages are recruited to the sites where the tumor develops.Under the guidance of different microenvironmental signals,macrophages would polarize into two functional phenotypes,named as classically activated macrophages(M1)and alternatively activated macrophages(M2).Contrary to the anti-tumor effect of M1,M2 exerts anti-inflammatory and tumorigenic characters.In progressive tumor,M2 tumor-associated macrophages(TAMs)are in the majority,being vital regulators reacting upon TME.This review elaborates on the role of TAMs in tumor progression.Furthermore,prospective macrophage-focused therapeutic strategies,including drugs not only in clinical trials but also at primary research stages,are summarized followed by a discussion about their clinical application values.Nanoparticulate systems with efficient drug delivery and improved antitumor effect are also summed up in this article.
基金National Natural Science Foundation of China,Grant/Award Numbers:8187111473,8217113337。
文摘Multidimensional analyses have demonstrated the presence of a unique tumor microenvironment(TME)in liver cancer.Tumor-associated macrophages(TAMs)are among the most abundant immune cells infiltrating the TME and are present at all stages of liver cancer progression,and targeting TAMs has become one of the most favored immunotherapy strategies.In addition,macrophages and liver cancer cells have distinct origins.At the early stage of liver cancer,macrophages can provide a niche for the maintenance of liver cancer stem cells.In contrast,cancer stem cells(CSCs)or poorly differentiated tumor cells are key factors modulating macrophage activation.In the present review,we first propose the origin connection between precursor macrophages and liver cancer cells.Macrophages undergo dynamic phenotypic transition during carcinogenesis.In this course of such transition,it is critical to determine the appropriate timing for therapy and block specific markers to suppress protumoral TAMs.The present review provides a more detailed discussion of transition trends of such surface markers than previous reviews.Complex crosstalk occurs between TAMs and liver cancer cells.TAMs play indispensable roles in tumor progression,angiogenesis,and autophagy due to their heterogeneity and robust plasticity.In addition,macrophages in the TME interact with other immune cells by directing cell-to-cell contact or secreting various effector molecules.Similarly,tumor cells combined with other immune cells can drive macrophage recruitment and polarization.Despite the latest achievements and the advancements in treatment strategies following TAMs studies,comprehensive discussions on the communication between macrophages and cancer cells or immune cells in liver cancer are currently lacking.In this review,we discussed the interactions between TAMs and liver cancer cells(from cell origin to maturation),the latest therapeutic strategies(including chimeric antigen receptor macrophages),and critical clinical trials for hepatocellular carcinoma(HCC)and intrahepatic cholangiocar-cinoma(iCCA)to provide a rationale for further clinical investigation of TAMs as a potential target for treating patients with liver cancer.
基金National Key Research and Development Program of China(No. 2021YFE0110600)National Natural Science Foundation of China(Nos. 91942314, 82072578, 82002564, and 81872333)
文摘Tumor-associated macrophages(TAMs)are an essential proportion of tumor-infiltrating immune cells in the tumor microenvironment(TME)and have immunosuppressive functions.The high plasticity and corresponding phenotypic transformation of TAMs facilitate oncogenesis and progression,and suppress antineoplastic responses.Due to the uncontrolled proliferation of tumor cells,metabolism homeostasis is regulated,leading to a series of alterations in the metabolite profiles in the TME,which have a commensurate influence on immune cells.Metabolic reprogramming of the TME has a profound impact on the polarization and function of TAMs,and can alter their metabolic profiles.TAMs undergo a series of metabolic reprogramming processes,involving glucose,lipid,and amino acid metabolism,and other metabolic pathways,which terminally promote the development of the immunosuppressive phenotype.TAMs express a pro-tumor phenotype by increasing glycolysis,fatty acid oxidation,cholesterol efflux,and arginine,tryptophan,glutamate,and glutamine metabolism.Previous studies on the metabolism of TAMs demonstrated that metabolic reprogramming has intimate crosstalk with anti-tumor or pro-tumor phenotypes and is crucial for the function of TAMs themselves.Targeting metabolism-related pathways is emerging as a promising therapeutic modality because of the massive metabolic remodeling that occurs in malignant cells and TAMs.Evidence reveals that the efficacy of immune checkpoint inhibitors is improved when combined with therapeutic strategies targeting metabolism-related pathways.In-depth research on metabolic reprogramming and potential therapeutic targets provides more options for anti-tumor treatment and creates new directions for the development of new immunotherapy methods.In this review,we elucidate the metabolic reprogramming of TAMs and explore how they sustain immunosuppressive phenotypes to provide a perspective for potential metabolic therapies.
基金the Excellent Youth Foundation of the Sichuan Scientific Committee Grant in China(No.2019JDJQ008)the National Natural Science Foundation for Regional Innovation and Development(No.U19A2003).
文摘The immunosuppressive tumor microenvironment(TME)is crucial in the occurrence of tumorigenesis,metastasis,and drug resistance.Among all stromal cells,tumor-associated macrophages(TAMs)are recognized as vital components causing the TME to be favorable for cancer cells and are also main targets in cancer immunotherapy.To date,nanoparticle(NP)-based drug delivery systems,as new technology platforms,have exhibited considerable advantages,such as targeted drug delivery at tumor sites,enhanced drug transport efficiency,and controllable drug release profiles,which provide new approaches for cancer therapy.Regarding TAM-targeting nanoparticles,various therapeutic strategies have been developed by varying their design,namely,by blocking TAM recruitment,promoting TAM transformation,and directly diminishing existing TAMs.In the current review,we provide a brief overview of the role of TAMs in the tumor microenvironment and their functions and highlight strategies for TAM targeting.Moreover,the applications of nanoparticles in targeting TAMs to improve cancer therapeutic efficiency are summarized.
文摘Gliomas,the most common primary tumors in the central nervous system(CNS),can be categorized into 4 grades according to the World Health Organization.The most malignant glioma type is gradeⅣ,also named glioblastoma multiforme(GBM).However,the standard treatment of concurrent temozolomide(TMZ)chemotherapy and radiotherapy after maximum resection does not improve overall survival in patients with GBM.Targeting components of the CNS microenvironment represents a new strategy for improving the efficacy of glioma treatment.Most recent studies focused on T cells.However,there is a growing body of evidence that tumor-associated macrophages(TAMs)play an important role in tumor progression and can be regulated by a wide array of cytokines or chemokines.New TAM-associated immunotherapies may improve clinical outcomes by blocking tumor progression and prolonging survival.However,understanding the exact roles and possible mechanisms of TAMs in the tumor environment is necessary for developing this promising therapeutic target and identifying potential diagnostic markers for improved prognosis.This review summarizes the possible interactions between TAMs and glioma progression and discusses the potential therapeutic directions for TAM-associated immunotherapies.
基金National Key Research and Development Plan,Grant/Award Number:2017YFA0506000Guangdong Basic and Applied Basic Research Foundation,Grant/Award Number:2021B1515120016+1 种基金National Natural Science Foundation of China,Grant/Award Number:82072822the Key Research and Development Program of Jiangsu Province,China-Social Development Projects,Grant/Award Number:BE2020687。
文摘Background:Interleukin-15(IL-15)is a promising immunotherapeutic agent owing to its powerful immune-activating effects.However,the clinical benefits of these treatments are limited.Crosstalk between tumor cells and immune cells plays an important role in immune escape and immunotherapy drug resistance.Herein,this study aimed to obtain in-depth understanding of crosstalk in the tumor microenvironment for providing potential therapeutic strategies to prevent tumor progression.Methods:T-cell killing assays and co-culture models were developed to determine the role of crosstalk between macrophages and tumor cells in breast cancer resistant to IL-15.Western blotting,histological analysis,CRISPR-Cas9 knockout,multi-parameter flow cytometry,and tumor cell-macrophage co-injection mouse models were developed to examine the mechanism by which IL-15Rα^(+)tumor-associated macrophages(TAMs)regulate breast cancer cell resistance to IL-15.Results:We found thatmacrophages contributed to the resistance of tumor cells to IL-15,and tumor cells induced macrophages to express high levels of theαsubunit of the IL-15 receptor(IL-15Rα).Further investigation showed that IL-15Rα^(+)TAMs reduced the protein levels of chemokine CX3C chemokine ligand 1(CX3CL1)in tumor cells to inhibit the recruitment of CD8^(+)T cells by releasing the IL-15/IL-15Rαcomplex(IL-15Rc).Administration of an IL-15Rc blocking peptide markedly suppressed breast tumor growth and overcame the resistance of cancer cells to anti-programmed cell death protein 1(PD-1)antibody immunotherapy.Interestingly,Granulocyte-macrophage colony-stimulating factor(GMCSF)inducedγchain(γc)expression to promote tumor cell-macrophage crosstalk,which facilitated tumor resistance to IL-15.Additionally,we observed that the non-transcriptional regulatory function of hypoxia inducible factor-1alpha(HIF-1α)was essential for IL-15Rc to regulateCX3CL1 expression in tumor cells.Conclusions:The IL-15Rc-HIF-1α-CX3CL1 signaling pathway serves as a crosstalk between macrophages and tumor cells in the tumormicroenvironment of breast cancer.Targeting this pathway may provide a potential therapeutic strategy for enhancing the efficacy of cancer immunotherapy.
