Objective Elevated myeloid-derived suppressor cells(MDSCs)in many malignancies are associated with the increased risk for metastases and poor prognosis.Therefore,a mouse model of intraocular melanoma was established t...Objective Elevated myeloid-derived suppressor cells(MDSCs)in many malignancies are associated with the increased risk for metastases and poor prognosis.Therefore,a mouse model of intraocular melanoma was established to explore how MDSCs influence liver metastases.Methods In this study,murine B16LS melanoma cells were transplanted into the posterior compartment(PC)of the eye of C57BL/6 mice.Leucocytes from the liver of naive mice and mice bearing melanoma liver metastasis were isolated using isotonic Percoll centrifugation,examined by flow cytometry for their expression of Gr1,CD11b,F4/80,RAE-1,and Mult-1,and further isolated for MDSCs and natural killer(NK)cells.The effects of MDSCs on NK cells were tested by coculturing and assessing the ability of NK cells to produce interferon-gamma(IFN-γ)by ELISA and NK cell cytotoxicity by 3H-thymidine incorporation assay.The impact of IFN-γon liver metastases was examined via selectively depleting IFN-γin vivo.Results The results showed that mice with liver metastases had increased levels of CD11b+Gr1+F4/80+as well as CD11b+Gr1+F4/80−MDSCs.MDSCs significantly enhanced the generation of IFN-γtogether with the cytotoxicity of the NK cells.Furthermore,these effects were cell-cell contact-dependent.Although IFN-γwas not of a toxic nature to the melanoma cells,it profoundly inhibited B16LS cell proliferation.Depleting IFN-γin vivo led to increased liver metastases.Conclusion All these findings first revealed that MDSCs accumulated in liver metastasis of intraocular melanoma could activate the NK cells to produce an effective anti-tumor immune response.Thus,the MDSCs’performance in different tumor models would need more investigation to boost current immunotherapy modalities.展开更多
Gastrointestinal(GI)cancers are one of the most common malignancies worldwide,with high rates of morbidity and mortality.Myeloid-derived suppressor cells(MDSCs)are major components of the tumor microenvironment(TME).M...Gastrointestinal(GI)cancers are one of the most common malignancies worldwide,with high rates of morbidity and mortality.Myeloid-derived suppressor cells(MDSCs)are major components of the tumor microenvironment(TME).MDSCs facilitate the transformation of premalignant cells and play roles in tumor growth and metastasis.Moreover,in patients with GI malignancies,MDSCs can lead to the suppression of T cells and natural killer cells.Accordingly,a better understanding of the role and mechanism of action of MDSCs in the TME will aid in the development of novel immune-targeted therapies.展开更多
Severe immunosuppression is a hallmark of colorectal cancer(CRC).Myeloid-derived suppressor cells(MDSCs),one of the most abundant components of the tumor stroma,play an important role in the invasion,metastasis,and im...Severe immunosuppression is a hallmark of colorectal cancer(CRC).Myeloid-derived suppressor cells(MDSCs),one of the most abundant components of the tumor stroma,play an important role in the invasion,metastasis,and immune escape of CRC.MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells,including T and natural killer cells,as well as by inducing the proliferation of immunosuppressive cells,such as regulatory T cells and tumor-associated macrophages,which,in turn,promote the growth of cancer cells.Thus,MDSCs are key contributors to the emergence of an immunosup-pressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity.In this narrative review,we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment,the current therapeutic approaches and technologies targeting MDSCs,and the therapeutic potential of modulating MDSCs in CRC treatment.This study provides ideas and methods to enhance survival rates in patients with CRC.展开更多
Glioblastoma(GBM)is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment(TME).In this environment,myeloid cells,such as myeloid-derived suppressor cells(MDSCs),play a pivotal rol...Glioblastoma(GBM)is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment(TME).In this environment,myeloid cells,such as myeloid-derived suppressor cells(MDSCs),play a pivotal role in suppressing antitumor immunity.Lipometabolism is closely related to the function of myeloid cells.Here,our study reports that acetyl-CoA acetyltransferase 1(ACAT1),the key enzyme of fatty acid oxidation(FAO)and ketogenesis,is significantly downregulated in the MDSCs infiltrated in GBM patients.To investigate the effects of ACAT1 on myeloid cells,we generated mice with myeloid-specific(LyzM-cre)depletion of ACAT1.The results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and orthotopically.The mechanism behind this effect is elevated secretion of C-X-C motif ligand 1(CXCLI)of macrophages(Mo).Overall,our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.展开更多
Gastrointestinal(GI)cancer encompasses a range ofmalignancies that originate in the digestive system,which together represent the most common form of cancer diagnosed worldwide.However,despite numerous advances in bot...Gastrointestinal(GI)cancer encompasses a range ofmalignancies that originate in the digestive system,which together represent the most common form of cancer diagnosed worldwide.However,despite numerous advances in both diagnostics and treatment,the incidence and mortality rate of GI cancer are on the rise.Myeloid-derived suppressor cells(MDSCs)are a heterogeneous population of immature myeloid cells that increase in number under certain pathological conditions,such as infection and inflammation,and this expansion is of particular relevance to cancer.MDSCs are heavily involved in the regulation of the immune system and act to dampen its response to tumors,favoring the escape of tumor cells from immunosurveillance and increasing both metastasis and recurrence.Several recent studies have supported the use of MDSCs as a prognostic and predictive biomarker in patientswith cancer,and potentially as a novel treatment target.In the present review,the mechanisms underlying the immunosuppressive functions of MDSCs are described,and recent researches concerning the involvement of MDSCs in the progression,prognosis,and therapies of GI cancer are reviewed.The aim of this work was to present the development of novel treatments targeting MDSCs in GI cancer in the hope of improving outcomes for patients with this condition.展开更多
The maternal immune system is vital in maintaining immunotolerance to the semiallogeneic fetus for a successful pregnancy.Although studies have shown that myeloid-derived suppressor cells(MDSCs)play an important role ...The maternal immune system is vital in maintaining immunotolerance to the semiallogeneic fetus for a successful pregnancy.Although studies have shown that myeloid-derived suppressor cells(MDSCs)play an important role in maintaining feto-maternal tolerance,little is known about the role of MDSCs in pregnancies with intrauterine growth retardation(IUGR).Here,we reported that the activation of polymorphonuclear myeloid-derived suppressor cells(PMN-MDSCs)during pregnancy was closely associated with fetal growth.In humans,class E scavenger receptor 1(SR-E1),a distinct marker for human PMN-MDSCs,was used to investigate PMN-MDSC function during pregnancy.Continuous activation of SR-E1+PMN-MDSCs was observed in all stages of pregnancy,accompanied by high cellular levels of ROS and arginase-1 activity,mediated through STAT6 signaling.However,SR-E1+PMN-MDSCs in pregnancies with IUGR showed significantly lower suppressive activity,lower arginase-1 activity and ROS levels,and decreased STAT6 phosphorylation level,which were accompanied by an increase in inflammatory factors,compared with those in normal pregnancies.Moreover,the population of SR-E1+PMN-MDSCs was negatively correlated with the adverse outcomes of newborns from pregnancies with IUGR.In mice,decreases in cell population,suppressive activity,target expression levels,and STAT6 phosphorylation levels were also observed in the pregnancies with IUGR compared with the normal pregnancies,which were rescued by the adoptive transfer of PMN-MDSCs from pregnant mice.Interestingly,the growth-promoting factors(GPFs)secreted by placental PMN-MDSCs in both humans and mice play a vital role in fetal development.These findings collectively support that PMN-MDSCs have another new role in pregnancy,which can improve adverse neonatal outcomes.展开更多
Numerous recent studies have shown that myeloid-derived suppressor cells(MDSCs),a strongly heterogeneous population of immunosuppressive cells,are dysregulated in the presence of many cancers.MDSCs present different p...Numerous recent studies have shown that myeloid-derived suppressor cells(MDSCs),a strongly heterogeneous population of immunosuppressive cells,are dysregulated in the presence of many cancers.MDSCs present different phenotypes and play prominent roles in the tumor microenvironment.To date,gene therapies targeting MDSCs are the most innovative and flexible methods to specifically modify the tumor microenvironment.Here,we summarize current studies related to the phenotypes,functions,and mechanisms of MDSCs and explore the therapeutic landscape of chemokines that affect the balance between subpopulations of MDSCs.展开更多
Objective To explore the possible role and clinical implications of myeloid-derived suppressor cells(MDSC)in the peripheral blood of patients with hepatitis B virus(HBV)-related acute-on-chronic liver failure(HBVACLF)...Objective To explore the possible role and clinical implications of myeloid-derived suppressor cells(MDSC)in the peripheral blood of patients with hepatitis B virus(HBV)-related acute-on-chronic liver failure(HBVACLF).Methods A total of 25 HBV-ACLF patients展开更多
Background:High agglomeration of myeloid-derived suppressor cells(MDSCs)in neuroblastoma(NB)impeded therapeutic effects.This study aimed to investigate the role and mechanism of targeted inhibition of MDSCs by low-dos...Background:High agglomeration of myeloid-derived suppressor cells(MDSCs)in neuroblastoma(NB)impeded therapeutic effects.This study aimed to investigate the role and mechanism of targeted inhibition of MDSCs by low-dose doxorubicin(DOX)to enhance immune efficacy in NB.Methods:Bagg albino(BALB/c)mice were used as tumor-bearing mouse models by injecting Neuro-2a cells,and MDSCs were eliminated by DOX or dopamine(DA)administration.Tumor-bearing mice were randomly divided into 2.5 mg/kg DOX,5.0 mg/kg DOX,50.0 mg/kg DA,and control groups(n=20).The optimal drug and its concentration for MDSC inhibition were selected according to tumor inhibition.NB antigen-specific cytotoxic T cells(CTLs)were prepared.Tumor-bearing mice were randomly divided into DOX,CTL,anti-ganglioside(GD2),DOX+CTL,DOX+anti-GD2,and control groups.Following low-dose DOX administration,immunotherapy was applied.The levels of human leukocyte antigen(HLA)-I,CD8,interleukin(IL)-2 and interferon(IFN)-γin peripheral blood,CTLs,T-helper 1(Th1)/Th2 cytokines,perforin,granzyme and tumor growth were compared among the groups.The Wilcoxon two-sample test and repeated-measures analysis of variance were used to analyze results.Results:The slowest tumor growth(F=6.095,P=0.018)and strongest MDSC inhibition(F=14.632,P=0.001)were observed in 2.5 mg/kg DOX group.Proliferation of T cells was increased(F=448.721,P<0.001)and then decreased(F=2.047,P=0.186).After low-dose DOX administration,HLA-I(F=222.489),CD8(F=271.686),Th1/Th2 cytokines,CD4^(+)and CD8^(+)lymphocytes,granzyme(F=2376.475)and perforin(F=488.531)in tumor,IL-2(F=62.951)and IFN-γ(F=240.709)in peripheral blood of each immunotherapy group were all higher compared with the control group(all ofP values<0.05).The most significant increases in the aforementioned indexes and the most notable tumor growth inhibition were observed in DOX+anti-GD2 and DOX+CTL groups.Conclusions:Low-dose DOX can be used as a potent immunomodulatory agent that selectively impairs MDSC-induced immunosuppression,thereby fostering immune efficacy in NB.展开更多
Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indi...Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking.Methods We adopted cross-species,single-cell RNA sequencing(scRNA-seq)analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis.Flow cytometry,laser scanning confocal microscopy(LSCM)imaging and Western blotting were applied to identify the presence of S100A9^(+)monocytes at protein level.To interrogate the immunosuppressive function of this subset,splenic monocytes isolated from septic wild-type or S100a9^(–/–)mice were co-cultured with naive CD4^(+)T cells,followed by proliferative assay.Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage.Results scRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis,for which distinct monocyte subsets were enriched in disparate subclusters of septic patients.We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR(HLA-DR),which were prominently enriched in septic patients and might exert immunosuppressive function.By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments,we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice,corresponding to HLA-DR^(low)S100A^(high)monocytes in human sepsis.Moreover,we found that S100A9^(+)monocytes exhibited profound immunosuppressive function on CD4^(+)T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression.Conclusions This study identifies HLA-DR^(low)S100A^(high)monocytes correlated with immunosuppressive state upon septic challenge,inhibition of which can markedly mitigate sepsis-induced immune depression,thereby providing a novel therapeutic strategy for the management of sepsis.展开更多
Myeloid-derived suppressor cells(MDSCs)are a heterogeneous population of immature cells and natural inhibitors of adaptive immunity.Intracellular metabolic changes in MDSCs exert a direct immunological influence on th...Myeloid-derived suppressor cells(MDSCs)are a heterogeneous population of immature cells and natural inhibitors of adaptive immunity.Intracellular metabolic changes in MDSCs exert a direct immunological influence on their suppressive activity.Our previous study demonstrated that high-dose dexamethasone(HD-DXM)corrected the functional impairment of MDSCs in immune thrombocytopenia(ITP);however,the MDSC population was not restored in nonresponders,and the mechanism remained unclear.In this study,altered mitochondrial physiology and reduced mitochondrial gene transcription were detected in MDSCs from HD-DXM nonresponders,accompanied by decreased levels of carnitine palmitoyltransferase-1(CPT-1),a rate-limiting enzyme in fatty acid oxidation(FAO).Blockade of FAO with a CPT-1 inhibitor abolished the immunosuppressive function of MDSCs in HD-DXM responders.We also report that MDSCs from ITP patients had lower expression of the glucocorticoid receptor(GR),which can translocate into mitochondria to regulate the transcription of mitochondrial DNA(mtDNA)as well as the level of oxidative phosphorylation.It was confirmed that the expression of CPT-1 and mtDNA-encoded genes was downregulated in GR-siRNA-treated murine MDSCs.Finally,by establishing murine models of active and passive ITP via adoptive transfer of DXM-modulated MDSCs,we confirmed that GR-silenced MDSCs failed to alleviate thrombocytopenia in mice with ITP.In conclusion,our study indicated that impaired aerobic metabolism in MDSCs participates in the pathogenesis of glucocorticoid resistance in ITP and that intact control of MDSC metabolism by GR contributes to the homeostatic regulation of immunosuppressive cell function.展开更多
Myeloid-derived suppressor cells(MDSCs)comprise heterogeneous myeloid cell populations with immunosuppressive capacity that contribute to immune regulation and tolerance induction.We previously reported impaired MDSC ...Myeloid-derived suppressor cells(MDSCs)comprise heterogeneous myeloid cell populations with immunosuppressive capacity that contribute to immune regulation and tolerance induction.We previously reported impaired MDSC function in patients with primary Sjögren’s syndrome(pSS)and mice with experimental SS(ESS).However,the molecular mechanisms underlying MDSC dysfunction remain largely unclear.In this study,we first found that aryl hydrocarbon receptor(AhR)was highly expressed by human and murine polymorphonuclear MDSCs(PMN-MDSCs).Indole-3-propionic acid(IPA),a natural AhR ligand produced from dietary tryptophan,significantly promoted PMN-MDSC differentiation and suppressive function on CD4^(+)T cells.In contrast,feeding a tryptophan-free diet resulted in a decreased PMN-MDSC response,a phenotype that could be reversed by IPA supplementation.The functional importance of PMN-MDSCs was demonstrated in ESS mice by using a cell-depletion approach.Notably,AhR expression was reduced in PMN-MDSCs during ESS development,while AhR antagonism resulted in exacerbated ESS pathology and dysregulated T effector cells,which could be phenocopied by a tryptophan-free diet.Interferon regulatory factor 4(IRF4),a repressive transcription factor,was upregulated in PMN-MDSCs during ESS progression.Chromatin immunoprecipitation analysis revealed that IRF4 could bind to the promoter region of AhR,while IRF4 deficiency markedly enhanced AhR-mediated PMN-MDSC responses.Furthermore,dietary supplementation with IPA markedly ameliorated salivary glandular pathology in ESS mice with restored MDSC immunosuppressive function.Together,our results identify a novel function of AhR in modulating the PMN-MDSC response and demonstrate the therapeutic potential of targeting AhR for the treatment of pSS.展开更多
Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed ...Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis,as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast cancer.During this process,both the immunosuppressive monocytic-(M-)and granulocytic-(G-)myeloid-derived suppressor cell(MDSC)decreased,accompanied by an increase in interleukin(IL)7R^(+)and granzyme B^(+)T cells in the tumor microenvironment.Interestingly,we observed that Ly6G^(low)G-MDSC sharply decreased after fasting treatment,and the cell surface markers and protein mass spectrometry data showed potential therapeutic targets.Mechanistic investigation revealed that glucose metabolism restriction suppressed the splenic granulocytemonocyte progenitor and the generation of colony-stimulating factors and IL-6,which both contributed to the accumulation of G-MDSC.On the other hand,glucose metabolism restriction can directly induce the apoptosis of Ly6G^(low)G-MDSC,but not Ly6G^(high)subsets.In summary,these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3^(+)T cells,providing potential solutions for enhancing immune-based cancer interventions.展开更多
Objective: We aimed to investigate the prognostic value of neutrophil-to-lymphocyte ratio(NLR) and myeloidderived suppressor cells(MDSCs) in gastric cancer patients treated with second-line ramucirumab plus paclitaxel...Objective: We aimed to investigate the prognostic value of neutrophil-to-lymphocyte ratio(NLR) and myeloidderived suppressor cells(MDSCs) in gastric cancer patients treated with second-line ramucirumab plus paclitaxel.Methods: A total of 116 patients with advanced or metastatic gastric cancer who receive ramucirumab plus paclitaxel were prospectively enrolled. Fresh blood samples were collected before and after treatment, and flow cytometry was performed to assess the proportions of monocytic(m MDSCs) and granulocytic MDSCs(g MDSCs).Results: Median age was 58 years and 71(61.2%) patients were male. A baseline NLR≥2.94 was associated with significantly poorer progression-free survival(PFS) and overall survival(OS) vs. an NLR<2.94(P=0.011 and P=0.002, respectively). In multivariate analysis, an NLR≥2.94 was independently associated with poorer PFS[hazard ratio(HR)=1.58;95% confidence interval(95% CI): 1.01-2.49, P=0.046] and OS(HR=1.77;95% CI:1.04-3.04, P=0.036). While m MDSC counts did not significantly change following two cycles of therapy(P=0.530),g MDSC counts decreased significantly after two treatment cycles(P=0.025) but tended to increase in patients with progressive disease after two treatment cycles(P=0.098). A progressive increase in g MDSC counts(≥44%) was associated with a significantly shorter PFS and OS vs. a g MDSC count increase <44%(P=0.001 and P=0.003,respectively).Conclusions: The baseline NLR may help guide clinical decisions during ramucirumab plus paclitaxel therapy for gastric cancer. Our g MDSC kinetics data warrant further clinical validation and mechanistic investigation.展开更多
The dynamic interplay between tumor cells and immune cells in the microenvironment plays a crucial role in determining disease severity and therapeutic outcome in cancer.Myeloid cells are the most abundantly available...The dynamic interplay between tumor cells and immune cells in the microenvironment plays a crucial role in determining disease severity and therapeutic outcome in cancer.Myeloid cells are the most abundantly available cell population in the tumor microenvironment.Myeloid cells have been shown to exist in diverse phenotypes and play both antitumoral and protumoral roles in cancer.Understanding the biology of myeloid cells can lay the foundation for the development of therapeutic strategies aimed at enhancing the antitumoral role of myeloid cells.This article presents an overview of the role of myeloid cells in tumor development and various mechanisms by which myeloid cells aid tumor progression.Existing drugs against cancer that utilize myeloid cells and the role of myeloid cells in drug resistance are also discussed.展开更多
Neutrophils,the most abundant leukocytes in human blood,are essential fighter immune cells against microbial infection.Based on the finding that neutrophils can either restrict or promote cancer progression,tumor-asso...Neutrophils,the most abundant leukocytes in human blood,are essential fighter immune cells against microbial infection.Based on the finding that neutrophils can either restrict or promote cancer progression,tumor-associated neutrophils(TAN)are classified into anti-tumor N1 and pro-tumor N2 subsets.One of the major mechanisms underlying the tumor-promoting function of N2-TANs is suppression of adaptive immune cells,in particular,cytotoxic T lymphocytes.Currently,no established methodologies are available that can unequivocally distinguish immunosuppressive TANs and granulocytic/polymorphonuclear myeloid-derived suppressor cells(G/PMN-MDSC).In view of the critical role of PMN-MDSCs in immune evasion and resistance to cancer immunotherapy,as established from data obtained with diverse cancer models,therapeutic strategies targeting these cells have been actively developed to enhance the efficacy of immunotherapy.Here,we have reviewed the available literature on strategies targeting PMN-MDSCs and summarized the findings into four categories:(1)depletion of existing PMN-MDSCs,(2)blockade of the development of PMNMDSCs,(3)blockade of PMN-MDSC recruitment,(4)inhibition of immunosuppressive function.Owing to their high mobility to inflamed organs and ability to trespass the blood-brain barrier,neutrophils are outstanding candidate carriers in nanoparticle-based therapies.Another attractive application of neutrophils in cancer therapy is the use of neutrophil membrane-derived nanovesicles as a surrogate of extracellular vesicles for more efficient and scalable drug delivery.In the second part of the review,we have highlighted recent advances in the field of neutrophil-based cancer drug delivery.Overall,we believe that neutrophil-based therapeutics are a rapidly growing area of cancer therapy with significant potential benefits.展开更多
A 70-year-old female with metastatic cutaneous squamous cell carcinoma(cSCC)and low-grade non-Hodgkin’s lymphoma,not amenable to cisplatin combination therapy,was treated with cyclophoshamide(Cyc)-fluorouracil(FU)-in...A 70-year-old female with metastatic cutaneous squamous cell carcinoma(cSCC)and low-grade non-Hodgkin’s lymphoma,not amenable to cisplatin combination therapy,was treated with cyclophoshamide(Cyc)-fluorouracil(FU)-interleukin-2(IL-2)in light of high tumor immunogenicity and the potential activity of this regimen.Cyc 300 mg/m^(2)and FU 500 mg/m^(2)intravenously on day 1 and IL-24.5 MIU/day on days 3-6 and 17-20 subcutaneously every 4 weeks;Carboplatin(C)AUC 2 and paclitaxel(P)85 mg/m^(2)on days 1,8 and 15±capecitabine(Cape)every 4 weeks.After partial remission(PR)of lung metastases and local control with two cycles of first therapy followed by PR with five cycles of CP±Cape,right mastectomy was performed with evidence of viable tumor.Subsequently,the patient underwent 3 cycles of chlorambucil and is alive after 13 months of follow-up.Safety and activity of chemo-immunotherapy and salvage treatment can be achieved in cSCC.展开更多
The liver is an immunologically tolerant organ and a common metastatic site of multiple cancer types.Although a role for cancer cell invasion programs has been well characterized,whether and how liver-intrinsic factor...The liver is an immunologically tolerant organ and a common metastatic site of multiple cancer types.Although a role for cancer cell invasion programs has been well characterized,whether and how liver-intrinsic factors drive metastatic spread is incompletely understood.Here,we show that aberrantly activated hepatocyte-intrinsic cell cycle-related kinase(CCRK)signaling in chronic liver diseases is critical for cancer metastasis by reprogramming an immunosuppressive microenvironment.Using an inducible liverspecific transgenic model,we found that CCRK overexpression dramatically increased both B16F10 melanoma and MC38 colorectal cancer(CRC)metastasis to the liver,which was highly infiltrated by polymorphonuclear-myeloid-derived suppressor cells(PMNMDSCs)and lacking natural killer T(NKT)cells.Depletion of PMN-MDSCs in CCRK transgenic mice restored NKT cell levels and their interferon gamma production and reduced liver metastasis to 2.7% and 0.7%(metastatic tumor weights)in the melanoma and CRC models,respectively.Mechanistically,CCRK activated nuclear factor-kappa B(NF-κB)signaling to increase the PMN-MDSC trafficking chemokine C-X-C motif ligand 1(CXCL1),which was positively correlated with liver-infiltrating PMN-MDSC levels in CCRK transgenic mice.Accordingly,CRC liver metastasis patients exhibited hyperaaivation of hepatic CCRK/NF-κB/CXCL1 signaling,which was associated with accumulation of PMN-MDSCs and paucity of NKT cells compared to healthy liver transplantation donors.In summary,this study demonstrates that immunosuppressive reprogramming by hepatic CCRK signaling undermines antimetastatic immunosurveillance.Our findings offer new mechanistic insights and therapeutic targets for liver metastasis intervention.展开更多
There is growing recognition that neutrophils play an important role in cancer initiation, progression and metastasis. Although they are typically characterized as short-lived effector cells, neutrophils have been sho...There is growing recognition that neutrophils play an important role in cancer initiation, progression and metastasis. Although they are typically characterized as short-lived effector cells, neutrophils have been shown to acquire immunosuppressive and pro-tumorigenic functions that promote tumor progression and escape. As such, inhibition of their function or depletion of neutrophils are being explored as potential cancer therapies. However, growing evidence of neutrophil diversification in cancer and their potential anti-tumor roles raise many unresolved questions. Here, we review recent advances that address the definition,origin and function of neutrophils in cancer, and elaborate on obstacles that make the study of neutrophils challenging. We envision that this review will provide the groundwork for focused design of therapeutics that will specifically target "tumorreprogrammed" neutrophils while sparing normal neutrophils to improve patient outcomes.展开更多
Immune homeostasis is maintained by an adequate balance of myeloid and lymphoid responses.In chronic inflammatory states,including cancer,this balance is lost due to dramatic expansion of myeloid progenitors that fail...Immune homeostasis is maintained by an adequate balance of myeloid and lymphoid responses.In chronic inflammatory states,including cancer,this balance is lost due to dramatic expansion of myeloid progenitors that fail to mature to functional inflammatory neutrophils,macrophages,and dendritic cells(DCs),thus giving rise to a decline in the antitumor effector lymphoid response.Cancer-related inflammation orchestrates the production of hematopoietic growth factors and cytokines that perpetuate recruitment and activation of myeloid precursors,resulting in unresolved and chronic inflammation.This pathologic inflammation creates profound alterations in the intrinsic cellular metabolism of the myeloid progenitor pool,which is amplified by competition for essential nutrients and by hypoxia-induced metabolic rewiring at the tumor site.Therefore,persistent myelopoiesis and metabolic dysfunctions contribute to the development of cancer,as well as to the severity of a broad range of diseases,including metabolic syndrome and autoimmune and infectious diseases.The aims of this review are to(1)define the metabolic networks implicated in aberrant myelopoiesis observed in cancer patients,(2)discuss the mechanisms underlying these clinical manifestations and the impact of metabolic perturbations on clinical outcomes,and(3)explore new biomarkers and therapeutic strategies to restore immunometabolism and differentiation of myeloid cells towards an effector phenotype to increase host antitumor immunity.We propose that the profound metabolic alterations and associated transcriptional changes triggered by chronic and overactivated immune responses in myeloid cells represent critical factors influencing the balance between therapeutic efficacy and immune-related adverse effects(irAEs)for current therapeutic strategies,including immune checkpoint inhibitor(ICI)therapy.展开更多
基金supported by the Fundamental Research Funds for the Central Universities(No.2021yjsCXCY086).
文摘Objective Elevated myeloid-derived suppressor cells(MDSCs)in many malignancies are associated with the increased risk for metastases and poor prognosis.Therefore,a mouse model of intraocular melanoma was established to explore how MDSCs influence liver metastases.Methods In this study,murine B16LS melanoma cells were transplanted into the posterior compartment(PC)of the eye of C57BL/6 mice.Leucocytes from the liver of naive mice and mice bearing melanoma liver metastasis were isolated using isotonic Percoll centrifugation,examined by flow cytometry for their expression of Gr1,CD11b,F4/80,RAE-1,and Mult-1,and further isolated for MDSCs and natural killer(NK)cells.The effects of MDSCs on NK cells were tested by coculturing and assessing the ability of NK cells to produce interferon-gamma(IFN-γ)by ELISA and NK cell cytotoxicity by 3H-thymidine incorporation assay.The impact of IFN-γon liver metastases was examined via selectively depleting IFN-γin vivo.Results The results showed that mice with liver metastases had increased levels of CD11b+Gr1+F4/80+as well as CD11b+Gr1+F4/80−MDSCs.MDSCs significantly enhanced the generation of IFN-γtogether with the cytotoxicity of the NK cells.Furthermore,these effects were cell-cell contact-dependent.Although IFN-γwas not of a toxic nature to the melanoma cells,it profoundly inhibited B16LS cell proliferation.Depleting IFN-γin vivo led to increased liver metastases.Conclusion All these findings first revealed that MDSCs accumulated in liver metastasis of intraocular melanoma could activate the NK cells to produce an effective anti-tumor immune response.Thus,the MDSCs’performance in different tumor models would need more investigation to boost current immunotherapy modalities.
文摘Gastrointestinal(GI)cancers are one of the most common malignancies worldwide,with high rates of morbidity and mortality.Myeloid-derived suppressor cells(MDSCs)are major components of the tumor microenvironment(TME).MDSCs facilitate the transformation of premalignant cells and play roles in tumor growth and metastasis.Moreover,in patients with GI malignancies,MDSCs can lead to the suppression of T cells and natural killer cells.Accordingly,a better understanding of the role and mechanism of action of MDSCs in the TME will aid in the development of novel immune-targeted therapies.
基金Supported by National Natural Science Foundation of China,No.82320108022,No.82322076 and No.82104466.
文摘Severe immunosuppression is a hallmark of colorectal cancer(CRC).Myeloid-derived suppressor cells(MDSCs),one of the most abundant components of the tumor stroma,play an important role in the invasion,metastasis,and immune escape of CRC.MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells,including T and natural killer cells,as well as by inducing the proliferation of immunosuppressive cells,such as regulatory T cells and tumor-associated macrophages,which,in turn,promote the growth of cancer cells.Thus,MDSCs are key contributors to the emergence of an immunosup-pressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity.In this narrative review,we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment,the current therapeutic approaches and technologies targeting MDSCs,and the therapeutic potential of modulating MDSCs in CRC treatment.This study provides ideas and methods to enhance survival rates in patients with CRC.
基金supported by National Key R&D Program of China(No.2019YFE0111800)National Natural Science Foundation of China(Nos.T2192972,81872923,and 81903904)the CAMS Innovation Fund(2022-I2M-1-014,China).
文摘Glioblastoma(GBM)is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment(TME).In this environment,myeloid cells,such as myeloid-derived suppressor cells(MDSCs),play a pivotal role in suppressing antitumor immunity.Lipometabolism is closely related to the function of myeloid cells.Here,our study reports that acetyl-CoA acetyltransferase 1(ACAT1),the key enzyme of fatty acid oxidation(FAO)and ketogenesis,is significantly downregulated in the MDSCs infiltrated in GBM patients.To investigate the effects of ACAT1 on myeloid cells,we generated mice with myeloid-specific(LyzM-cre)depletion of ACAT1.The results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and orthotopically.The mechanism behind this effect is elevated secretion of C-X-C motif ligand 1(CXCLI)of macrophages(Mo).Overall,our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.
基金National Natural Science Foundation of China,Grant/Award Numbers:81772957,82002546China Postdoctoral Science Foundation,Grant/Award Number:2020M672815+3 种基金National Key R&D Program of China,Grant/Award Number:2017YFA0503900Science and Technology Program of Guangdong Province in China,Grant/Award Number:2019B030301009Industry and Information Technology Foundation of Shenzhen,Grant/Award Number:20180309100135860SZU Top Ranking Project,Grant/Award Number:86000000210。
文摘Gastrointestinal(GI)cancer encompasses a range ofmalignancies that originate in the digestive system,which together represent the most common form of cancer diagnosed worldwide.However,despite numerous advances in both diagnostics and treatment,the incidence and mortality rate of GI cancer are on the rise.Myeloid-derived suppressor cells(MDSCs)are a heterogeneous population of immature myeloid cells that increase in number under certain pathological conditions,such as infection and inflammation,and this expansion is of particular relevance to cancer.MDSCs are heavily involved in the regulation of the immune system and act to dampen its response to tumors,favoring the escape of tumor cells from immunosurveillance and increasing both metastasis and recurrence.Several recent studies have supported the use of MDSCs as a prognostic and predictive biomarker in patientswith cancer,and potentially as a novel treatment target.In the present review,the mechanisms underlying the immunosuppressive functions of MDSCs are described,and recent researches concerning the involvement of MDSCs in the progression,prognosis,and therapies of GI cancer are reviewed.The aim of this work was to present the development of novel treatments targeting MDSCs in GI cancer in the hope of improving outcomes for patients with this condition.
基金supported by grants from the following institutions:the High-level Talent Start-up Funding of Southern Medical Universitythe National Natural Science Foundation of China(grant numbers:31700061,81971420 and 81991511)+2 种基金the Guangdong Special Support Program for Youth Science and Technology Innovation Talents(grant number:2019TQ05Y585)the National Natural Science Foundation of Guangdong(grant number:2019A1515011435)the Science and Technology Program of Guangzhou(grant number:201904010073).
文摘The maternal immune system is vital in maintaining immunotolerance to the semiallogeneic fetus for a successful pregnancy.Although studies have shown that myeloid-derived suppressor cells(MDSCs)play an important role in maintaining feto-maternal tolerance,little is known about the role of MDSCs in pregnancies with intrauterine growth retardation(IUGR).Here,we reported that the activation of polymorphonuclear myeloid-derived suppressor cells(PMN-MDSCs)during pregnancy was closely associated with fetal growth.In humans,class E scavenger receptor 1(SR-E1),a distinct marker for human PMN-MDSCs,was used to investigate PMN-MDSC function during pregnancy.Continuous activation of SR-E1+PMN-MDSCs was observed in all stages of pregnancy,accompanied by high cellular levels of ROS and arginase-1 activity,mediated through STAT6 signaling.However,SR-E1+PMN-MDSCs in pregnancies with IUGR showed significantly lower suppressive activity,lower arginase-1 activity and ROS levels,and decreased STAT6 phosphorylation level,which were accompanied by an increase in inflammatory factors,compared with those in normal pregnancies.Moreover,the population of SR-E1+PMN-MDSCs was negatively correlated with the adverse outcomes of newborns from pregnancies with IUGR.In mice,decreases in cell population,suppressive activity,target expression levels,and STAT6 phosphorylation levels were also observed in the pregnancies with IUGR compared with the normal pregnancies,which were rescued by the adoptive transfer of PMN-MDSCs from pregnant mice.Interestingly,the growth-promoting factors(GPFs)secreted by placental PMN-MDSCs in both humans and mice play a vital role in fetal development.These findings collectively support that PMN-MDSCs have another new role in pregnancy,which can improve adverse neonatal outcomes.
基金supported by grants from the National Natural Science Foundation of China(No.81773067,82073217,82073218,and 82003084)Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX05)+1 种基金Shanghai Municipal Key Clinical Specialty,CAMS Innovation Fund for Medical Sciences(CIFMS)(2019-I2 M-5-058)National Key R&D Program of China(2020YFE0202200).
文摘Numerous recent studies have shown that myeloid-derived suppressor cells(MDSCs),a strongly heterogeneous population of immunosuppressive cells,are dysregulated in the presence of many cancers.MDSCs present different phenotypes and play prominent roles in the tumor microenvironment.To date,gene therapies targeting MDSCs are the most innovative and flexible methods to specifically modify the tumor microenvironment.Here,we summarize current studies related to the phenotypes,functions,and mechanisms of MDSCs and explore the therapeutic landscape of chemokines that affect the balance between subpopulations of MDSCs.
文摘Objective To explore the possible role and clinical implications of myeloid-derived suppressor cells(MDSC)in the peripheral blood of patients with hepatitis B virus(HBV)-related acute-on-chronic liver failure(HBVACLF).Methods A total of 25 HBV-ACLF patients
基金National Natural Science Foundation of China(No.81472503)。
文摘Background:High agglomeration of myeloid-derived suppressor cells(MDSCs)in neuroblastoma(NB)impeded therapeutic effects.This study aimed to investigate the role and mechanism of targeted inhibition of MDSCs by low-dose doxorubicin(DOX)to enhance immune efficacy in NB.Methods:Bagg albino(BALB/c)mice were used as tumor-bearing mouse models by injecting Neuro-2a cells,and MDSCs were eliminated by DOX or dopamine(DA)administration.Tumor-bearing mice were randomly divided into 2.5 mg/kg DOX,5.0 mg/kg DOX,50.0 mg/kg DA,and control groups(n=20).The optimal drug and its concentration for MDSC inhibition were selected according to tumor inhibition.NB antigen-specific cytotoxic T cells(CTLs)were prepared.Tumor-bearing mice were randomly divided into DOX,CTL,anti-ganglioside(GD2),DOX+CTL,DOX+anti-GD2,and control groups.Following low-dose DOX administration,immunotherapy was applied.The levels of human leukocyte antigen(HLA)-I,CD8,interleukin(IL)-2 and interferon(IFN)-γin peripheral blood,CTLs,T-helper 1(Th1)/Th2 cytokines,perforin,granzyme and tumor growth were compared among the groups.The Wilcoxon two-sample test and repeated-measures analysis of variance were used to analyze results.Results:The slowest tumor growth(F=6.095,P=0.018)and strongest MDSC inhibition(F=14.632,P=0.001)were observed in 2.5 mg/kg DOX group.Proliferation of T cells was increased(F=448.721,P<0.001)and then decreased(F=2.047,P=0.186).After low-dose DOX administration,HLA-I(F=222.489),CD8(F=271.686),Th1/Th2 cytokines,CD4^(+)and CD8^(+)lymphocytes,granzyme(F=2376.475)and perforin(F=488.531)in tumor,IL-2(F=62.951)and IFN-γ(F=240.709)in peripheral blood of each immunotherapy group were all higher compared with the control group(all ofP values<0.05).The most significant increases in the aforementioned indexes and the most notable tumor growth inhibition were observed in DOX+anti-GD2 and DOX+CTL groups.Conclusions:Low-dose DOX can be used as a potent immunomodulatory agent that selectively impairs MDSC-induced immunosuppression,thereby fostering immune efficacy in NB.
基金supported by the Key Project of National Natural Science Foundation of China(82130062,82241062 and 81930057)the National Key Research and Development Program of China(2022YFA1104604)+1 种基金the Key Project of Military Medical Innovation Program of Chinese PLA(18CXZ026 and BLJ18J006)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-076)。
文摘Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking.Methods We adopted cross-species,single-cell RNA sequencing(scRNA-seq)analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis.Flow cytometry,laser scanning confocal microscopy(LSCM)imaging and Western blotting were applied to identify the presence of S100A9^(+)monocytes at protein level.To interrogate the immunosuppressive function of this subset,splenic monocytes isolated from septic wild-type or S100a9^(–/–)mice were co-cultured with naive CD4^(+)T cells,followed by proliferative assay.Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage.Results scRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis,for which distinct monocyte subsets were enriched in disparate subclusters of septic patients.We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR(HLA-DR),which were prominently enriched in septic patients and might exert immunosuppressive function.By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments,we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice,corresponding to HLA-DR^(low)S100A^(high)monocytes in human sepsis.Moreover,we found that S100A9^(+)monocytes exhibited profound immunosuppressive function on CD4^(+)T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression.Conclusions This study identifies HLA-DR^(low)S100A^(high)monocytes correlated with immunosuppressive state upon septic challenge,inhibition of which can markedly mitigate sepsis-induced immune depression,thereby providing a novel therapeutic strategy for the management of sepsis.
基金This work was supported by grants from the National Natural Science Foundation of China(Nos.81900121,81770133,81973994,and 81770114)Major Research Plan of National Natural Science Foundation of China(No.91942306)+3 种基金Clinical Research Center of Shandong University(No.2020SDUCRCC009)Graduate Education Reform Project of Shandong University(No.XYJG2020141)State Key Clinical Specialty of China for Blood DisordersYoung Taishan Scholar Foundation of Shandong Province(No.tsqn201909175).
文摘Myeloid-derived suppressor cells(MDSCs)are a heterogeneous population of immature cells and natural inhibitors of adaptive immunity.Intracellular metabolic changes in MDSCs exert a direct immunological influence on their suppressive activity.Our previous study demonstrated that high-dose dexamethasone(HD-DXM)corrected the functional impairment of MDSCs in immune thrombocytopenia(ITP);however,the MDSC population was not restored in nonresponders,and the mechanism remained unclear.In this study,altered mitochondrial physiology and reduced mitochondrial gene transcription were detected in MDSCs from HD-DXM nonresponders,accompanied by decreased levels of carnitine palmitoyltransferase-1(CPT-1),a rate-limiting enzyme in fatty acid oxidation(FAO).Blockade of FAO with a CPT-1 inhibitor abolished the immunosuppressive function of MDSCs in HD-DXM responders.We also report that MDSCs from ITP patients had lower expression of the glucocorticoid receptor(GR),which can translocate into mitochondria to regulate the transcription of mitochondrial DNA(mtDNA)as well as the level of oxidative phosphorylation.It was confirmed that the expression of CPT-1 and mtDNA-encoded genes was downregulated in GR-siRNA-treated murine MDSCs.Finally,by establishing murine models of active and passive ITP via adoptive transfer of DXM-modulated MDSCs,we confirmed that GR-silenced MDSCs failed to alleviate thrombocytopenia in mice with ITP.In conclusion,our study indicated that impaired aerobic metabolism in MDSCs participates in the pathogenesis of glucocorticoid resistance in ITP and that intact control of MDSC metabolism by GR contributes to the homeostatic regulation of immunosuppressive cell function.
基金supported by the Chongqing International Institute for Immunology (2020YJC10)the National Natural Science Foundation of China (NSFC) (82071817,81971542,and 82171771)+3 种基金the Hong Kong Research Grants Council General Research Fund (17113319 and 27111820)Theme-Based Research Scheme (T12-703/19 R)the Shenzhen Science and Technology Program (YCYJ20210324114602008)the Centre for Oncology and Immunology under the Health@InnoHK Initiative of the Innovation and Technology Commission,Hong Kong,China.
文摘Myeloid-derived suppressor cells(MDSCs)comprise heterogeneous myeloid cell populations with immunosuppressive capacity that contribute to immune regulation and tolerance induction.We previously reported impaired MDSC function in patients with primary Sjögren’s syndrome(pSS)and mice with experimental SS(ESS).However,the molecular mechanisms underlying MDSC dysfunction remain largely unclear.In this study,we first found that aryl hydrocarbon receptor(AhR)was highly expressed by human and murine polymorphonuclear MDSCs(PMN-MDSCs).Indole-3-propionic acid(IPA),a natural AhR ligand produced from dietary tryptophan,significantly promoted PMN-MDSC differentiation and suppressive function on CD4^(+)T cells.In contrast,feeding a tryptophan-free diet resulted in a decreased PMN-MDSC response,a phenotype that could be reversed by IPA supplementation.The functional importance of PMN-MDSCs was demonstrated in ESS mice by using a cell-depletion approach.Notably,AhR expression was reduced in PMN-MDSCs during ESS development,while AhR antagonism resulted in exacerbated ESS pathology and dysregulated T effector cells,which could be phenocopied by a tryptophan-free diet.Interferon regulatory factor 4(IRF4),a repressive transcription factor,was upregulated in PMN-MDSCs during ESS progression.Chromatin immunoprecipitation analysis revealed that IRF4 could bind to the promoter region of AhR,while IRF4 deficiency markedly enhanced AhR-mediated PMN-MDSC responses.Furthermore,dietary supplementation with IPA markedly ameliorated salivary glandular pathology in ESS mice with restored MDSC immunosuppressive function.Together,our results identify a novel function of AhR in modulating the PMN-MDSC response and demonstrate the therapeutic potential of targeting AhR for the treatment of pSS.
基金supported by the Postdoctoral Research Funds of Hebei Medical University(30705010016-3759)Natural Science Foundation of China(32272328)+4 种基金Natural Science Foundation of Hebei Province(B2022321001)National Key Research Project of Hebei Province(20375502D)Postdoctoral Research Project of Hebei Province(B2022003031)Science and Technology Research Program of Hebei Provincial Colleges(QN2023229)Hebei Provincial Key Laboratory of Nutrition and Health(2023YDYY-KF05)。
文摘Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis,as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast cancer.During this process,both the immunosuppressive monocytic-(M-)and granulocytic-(G-)myeloid-derived suppressor cell(MDSC)decreased,accompanied by an increase in interleukin(IL)7R^(+)and granzyme B^(+)T cells in the tumor microenvironment.Interestingly,we observed that Ly6G^(low)G-MDSC sharply decreased after fasting treatment,and the cell surface markers and protein mass spectrometry data showed potential therapeutic targets.Mechanistic investigation revealed that glucose metabolism restriction suppressed the splenic granulocytemonocyte progenitor and the generation of colony-stimulating factors and IL-6,which both contributed to the accumulation of G-MDSC.On the other hand,glucose metabolism restriction can directly induce the apoptosis of Ly6G^(low)G-MDSC,but not Ly6G^(high)subsets.In summary,these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3^(+)T cells,providing potential solutions for enhancing immune-based cancer interventions.
文摘Objective: We aimed to investigate the prognostic value of neutrophil-to-lymphocyte ratio(NLR) and myeloidderived suppressor cells(MDSCs) in gastric cancer patients treated with second-line ramucirumab plus paclitaxel.Methods: A total of 116 patients with advanced or metastatic gastric cancer who receive ramucirumab plus paclitaxel were prospectively enrolled. Fresh blood samples were collected before and after treatment, and flow cytometry was performed to assess the proportions of monocytic(m MDSCs) and granulocytic MDSCs(g MDSCs).Results: Median age was 58 years and 71(61.2%) patients were male. A baseline NLR≥2.94 was associated with significantly poorer progression-free survival(PFS) and overall survival(OS) vs. an NLR<2.94(P=0.011 and P=0.002, respectively). In multivariate analysis, an NLR≥2.94 was independently associated with poorer PFS[hazard ratio(HR)=1.58;95% confidence interval(95% CI): 1.01-2.49, P=0.046] and OS(HR=1.77;95% CI:1.04-3.04, P=0.036). While m MDSC counts did not significantly change following two cycles of therapy(P=0.530),g MDSC counts decreased significantly after two treatment cycles(P=0.025) but tended to increase in patients with progressive disease after two treatment cycles(P=0.098). A progressive increase in g MDSC counts(≥44%) was associated with a significantly shorter PFS and OS vs. a g MDSC count increase <44%(P=0.001 and P=0.003,respectively).Conclusions: The baseline NLR may help guide clinical decisions during ramucirumab plus paclitaxel therapy for gastric cancer. Our g MDSC kinetics data warrant further clinical validation and mechanistic investigation.
文摘The dynamic interplay between tumor cells and immune cells in the microenvironment plays a crucial role in determining disease severity and therapeutic outcome in cancer.Myeloid cells are the most abundantly available cell population in the tumor microenvironment.Myeloid cells have been shown to exist in diverse phenotypes and play both antitumoral and protumoral roles in cancer.Understanding the biology of myeloid cells can lay the foundation for the development of therapeutic strategies aimed at enhancing the antitumoral role of myeloid cells.This article presents an overview of the role of myeloid cells in tumor development and various mechanisms by which myeloid cells aid tumor progression.Existing drugs against cancer that utilize myeloid cells and the role of myeloid cells in drug resistance are also discussed.
基金partly supported by a graduate fellowship from China Scholarship Council(Grant No.201708340071)partly supported by a Career Catalyst Research Grant(Grant No.18548293)from the Susan G.Komen Foundation+1 种基金a Cancer Research Grant from the Mary Kay Foundationa Research Grant from the Elsa U.Pardee Foundation。
文摘Neutrophils,the most abundant leukocytes in human blood,are essential fighter immune cells against microbial infection.Based on the finding that neutrophils can either restrict or promote cancer progression,tumor-associated neutrophils(TAN)are classified into anti-tumor N1 and pro-tumor N2 subsets.One of the major mechanisms underlying the tumor-promoting function of N2-TANs is suppression of adaptive immune cells,in particular,cytotoxic T lymphocytes.Currently,no established methodologies are available that can unequivocally distinguish immunosuppressive TANs and granulocytic/polymorphonuclear myeloid-derived suppressor cells(G/PMN-MDSC).In view of the critical role of PMN-MDSCs in immune evasion and resistance to cancer immunotherapy,as established from data obtained with diverse cancer models,therapeutic strategies targeting these cells have been actively developed to enhance the efficacy of immunotherapy.Here,we have reviewed the available literature on strategies targeting PMN-MDSCs and summarized the findings into four categories:(1)depletion of existing PMN-MDSCs,(2)blockade of the development of PMNMDSCs,(3)blockade of PMN-MDSC recruitment,(4)inhibition of immunosuppressive function.Owing to their high mobility to inflamed organs and ability to trespass the blood-brain barrier,neutrophils are outstanding candidate carriers in nanoparticle-based therapies.Another attractive application of neutrophils in cancer therapy is the use of neutrophil membrane-derived nanovesicles as a surrogate of extracellular vesicles for more efficient and scalable drug delivery.In the second part of the review,we have highlighted recent advances in the field of neutrophil-based cancer drug delivery.Overall,we believe that neutrophil-based therapeutics are a rapidly growing area of cancer therapy with significant potential benefits.
文摘A 70-year-old female with metastatic cutaneous squamous cell carcinoma(cSCC)and low-grade non-Hodgkin’s lymphoma,not amenable to cisplatin combination therapy,was treated with cyclophoshamide(Cyc)-fluorouracil(FU)-interleukin-2(IL-2)in light of high tumor immunogenicity and the potential activity of this regimen.Cyc 300 mg/m^(2)and FU 500 mg/m^(2)intravenously on day 1 and IL-24.5 MIU/day on days 3-6 and 17-20 subcutaneously every 4 weeks;Carboplatin(C)AUC 2 and paclitaxel(P)85 mg/m^(2)on days 1,8 and 15±capecitabine(Cape)every 4 weeks.After partial remission(PR)of lung metastases and local control with two cycles of first therapy followed by PR with five cycles of CP±Cape,right mastectomy was performed with evidence of viable tumor.Subsequently,the patient underwent 3 cycles of chlorambucil and is alive after 13 months of follow-up.Safety and activity of chemo-immunotherapy and salvage treatment can be achieved in cSCC.
基金supported by the University Grants Committee through the Collaborative Research Fund(C4045-18W)Theme-based Research Schem e(T11-706/18-N)+2 种基金General Research Fund(14108219,14105419)the Li Ka Shing Foundationthe Terry Fox Foundation.
文摘The liver is an immunologically tolerant organ and a common metastatic site of multiple cancer types.Although a role for cancer cell invasion programs has been well characterized,whether and how liver-intrinsic factors drive metastatic spread is incompletely understood.Here,we show that aberrantly activated hepatocyte-intrinsic cell cycle-related kinase(CCRK)signaling in chronic liver diseases is critical for cancer metastasis by reprogramming an immunosuppressive microenvironment.Using an inducible liverspecific transgenic model,we found that CCRK overexpression dramatically increased both B16F10 melanoma and MC38 colorectal cancer(CRC)metastasis to the liver,which was highly infiltrated by polymorphonuclear-myeloid-derived suppressor cells(PMNMDSCs)and lacking natural killer T(NKT)cells.Depletion of PMN-MDSCs in CCRK transgenic mice restored NKT cell levels and their interferon gamma production and reduced liver metastasis to 2.7% and 0.7%(metastatic tumor weights)in the melanoma and CRC models,respectively.Mechanistically,CCRK activated nuclear factor-kappa B(NF-κB)signaling to increase the PMN-MDSC trafficking chemokine C-X-C motif ligand 1(CXCL1),which was positively correlated with liver-infiltrating PMN-MDSC levels in CCRK transgenic mice.Accordingly,CRC liver metastasis patients exhibited hyperaaivation of hepatic CCRK/NF-κB/CXCL1 signaling,which was associated with accumulation of PMN-MDSCs and paucity of NKT cells compared to healthy liver transplantation donors.In summary,this study demonstrates that immunosuppressive reprogramming by hepatic CCRK signaling undermines antimetastatic immunosurveillance.Our findings offer new mechanistic insights and therapeutic targets for liver metastasis intervention.
基金This work was supported by Singapore Immunology Network(SigN)core funding,A*STAR,Singapore to L.G.N.
文摘There is growing recognition that neutrophils play an important role in cancer initiation, progression and metastasis. Although they are typically characterized as short-lived effector cells, neutrophils have been shown to acquire immunosuppressive and pro-tumorigenic functions that promote tumor progression and escape. As such, inhibition of their function or depletion of neutrophils are being explored as potential cancer therapies. However, growing evidence of neutrophil diversification in cancer and their potential anti-tumor roles raise many unresolved questions. Here, we review recent advances that address the definition,origin and function of neutrophils in cancer, and elaborate on obstacles that make the study of neutrophils challenging. We envision that this review will provide the groundwork for focused design of therapeutics that will specifically target "tumorreprogrammed" neutrophils while sparing normal neutrophils to improve patient outcomes.
基金supported by the Associazione Italiana per la Ricerca sul Cancro(AIRC)(IG number 19885 to A.S.)AIRC 5x1000(number 22757)+1 种基金Fondazione Cariplo,and Ministero Universita’Ricerca(MIUR)(project:2017BA9LM5_001)Associazione"Augusto per la Vita",Novellara(RE)and Associazione"Medicine Rocks",Milano.
文摘Immune homeostasis is maintained by an adequate balance of myeloid and lymphoid responses.In chronic inflammatory states,including cancer,this balance is lost due to dramatic expansion of myeloid progenitors that fail to mature to functional inflammatory neutrophils,macrophages,and dendritic cells(DCs),thus giving rise to a decline in the antitumor effector lymphoid response.Cancer-related inflammation orchestrates the production of hematopoietic growth factors and cytokines that perpetuate recruitment and activation of myeloid precursors,resulting in unresolved and chronic inflammation.This pathologic inflammation creates profound alterations in the intrinsic cellular metabolism of the myeloid progenitor pool,which is amplified by competition for essential nutrients and by hypoxia-induced metabolic rewiring at the tumor site.Therefore,persistent myelopoiesis and metabolic dysfunctions contribute to the development of cancer,as well as to the severity of a broad range of diseases,including metabolic syndrome and autoimmune and infectious diseases.The aims of this review are to(1)define the metabolic networks implicated in aberrant myelopoiesis observed in cancer patients,(2)discuss the mechanisms underlying these clinical manifestations and the impact of metabolic perturbations on clinical outcomes,and(3)explore new biomarkers and therapeutic strategies to restore immunometabolism and differentiation of myeloid cells towards an effector phenotype to increase host antitumor immunity.We propose that the profound metabolic alterations and associated transcriptional changes triggered by chronic and overactivated immune responses in myeloid cells represent critical factors influencing the balance between therapeutic efficacy and immune-related adverse effects(irAEs)for current therapeutic strategies,including immune checkpoint inhibitor(ICI)therapy.
