The programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)signaling pathway is an important mechanism in tumor immune escape,and expression of PD-L1 on tumor cells has been reported more frequently.Howeve...The programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)signaling pathway is an important mechanism in tumor immune escape,and expression of PD-L1 on tumor cells has been reported more frequently.However,accumulating evidence suggests that PD-1/PD-L1 is also widely expressed on immune cells,and that regulation is also critical for tumor immune responses.In this review,we emphasized that under solid tumor conditions,the immunoregulatory effects of immune cells expressing PD-1 or PD-L1,affected the prognoses of cancer patients.Therefore,a better understanding of the mechanisms that regulate PD-1 or PD-L1 expression on immune cells would provide clear insights into the increased efficacy of anti-PD antibodies and the development of novel tumor immunotherapy strategies.展开更多
BACKGROUND Recurrent hepatocellular carcinoma(HCC)with inferior vena cava tumor thrombus is a great challenge for oncologists and has a poor prognosis.To date,the safety and efficacy of programmed cell death ligand 1(...BACKGROUND Recurrent hepatocellular carcinoma(HCC)with inferior vena cava tumor thrombus is a great challenge for oncologists and has a poor prognosis.To date,the safety and efficacy of programmed cell death ligand 1(PD-L1)inhibitors are still unknown.CASE SUMMARY A 59-year-old male was identified as having a tumor thrombus in the inferior vena cava 3 years after surgery.The patient underwent a second surgery and adjuvant chemotherapy.However,the level of alpha-fetoprotein was elevated after 2 mo,and lung metastases and mediastinal lymph node metastases were identified.The expression of PD-L1 in HCC and inferior vena cava tumor thrombus tissues was analyzed by immunohistochemistry.Then,the patient received atezolizumab immunotherapy.The level of alpha-fetoprotein dropped to normal,the mediastinal lymph node metastases decreased in size and the lung metastases disappeared after 3 mo of immunotherapy.The patient had no signs of recurrence at 21 mo of follow-up.A 60-year-old male underwent left hepatic tumor resection,inferior vena cava incision and thrombus removal,followed by regular chemotherapy.The patient developed lung and splenic metastases after surgery.Pembrolizumab was used for six courses,and the splenic metastasis shrank,after which splenectomy was performed.The patient continued to receive pembrolizumab for thirteen courses,and the lung metastases showed no progression.A 34-year-old male was diagnosed with liver cancer with inferior vena cava tumor thrombus.The patient underwent right hepatectomy and received tislelizumab for three courses.He is still receiving immunotherapy and in good condition.CONCLUSION Anti-PD-L1 therapy in HCC patients with inferior vena cava tumor thrombus and metastasis is associated with relatively good patient outcomes.展开更多
In recent years,a number of targeted therapeutic agents have achieved success in phase III trials in patients with advanced hepatocellular carcinoma(HCC),including sorafenib,lenvatinib,and regorafenib.Immunotherapy is...In recent years,a number of targeted therapeutic agents have achieved success in phase III trials in patients with advanced hepatocellular carcinoma(HCC),including sorafenib,lenvatinib,and regorafenib.Immunotherapy is considered to be an effective treatment for advanced HCC.Immune checkpoint inhibitors targeting programmed cell death 1(PD-1)/programmed cell death ligand 1(PDL1)are important antitumor immunotherapy agents that represent breakthroughs in the treatment of advanced HCC.However,treating advanced HCC is still a great challenge,and the need for new treatments remains urgent.This review briefly summarizes the research progress in the use of PD-1/PD-L1 inhibitors combined with targeted therapy for treating HCC.展开更多
Background:Programmed cell death 1(PD-1)and programmed cell death ligand 1(PD-L1)inhibitors have become integral elements within the current landscape of breast cancer treatment modalities;however,they are associ-ated...Background:Programmed cell death 1(PD-1)and programmed cell death ligand 1(PD-L1)inhibitors have become integral elements within the current landscape of breast cancer treatment modalities;however,they are associ-ated with interstitial lung disease(ILD),which is rare but potentially fatal.Notably,only a few studies have compared the difference in ILD incidence between PD-1 and PD-L1 inhibitors.Therefore,this study aimed to assess the discrepancies regarding ILD risk between the two immune checkpoint inhibitors.We also reported three cases of ILD after PD-1 inhibitor treatment.Methods:We comprehensively searched PubMed,EMBASE,and the Cochrane Library to identify clinical trials that investigated PD-1/PD-L1 inhibitor treatment for patients with breast cancer.Pooled overall estimates of incidence and risk ratio(RR)were calculated with a 95%confidence interval(CI),and a mirror group analysis was per-formed using eligible studies.Results:This meta-analysis included 29 studies with 4639 patients who received PD-1/PD-L1 inhibitor treatment.A higher ILD incidence was observed among 2508 patients treated with PD-1 inhibitors than among 2131 patients treated with PD-L1 inhibitors(0.05 vs.0.02).The mirror group analysis further revealed a higher ILD event risk in patients treated with PD-1 inhibitors than in those treated with PD-L1 inhibitors(RR=2.34,95%CI,1.13-4.82,P=0.02).Conclusion:Our findings suggest a greater risk of ILD with PD-1 inhibitors than with PD-L1 inhibitors.These findings are instrumental for clinicians in treatment deliberations,and the adoption of more structured diagnostic approaches and management protocols is necessary to mitigate the risk of ILD.展开更多
BACKGROUND The immunosuppressive capacity of mesenchymal stem cells(MSCs)is dependent on the“license”of several proinflammatory factors to express immunosuppressive factors such as programmed cell death 1 ligand 1(P...BACKGROUND The immunosuppressive capacity of mesenchymal stem cells(MSCs)is dependent on the“license”of several proinflammatory factors to express immunosuppressive factors such as programmed cell death 1 ligand 1(PD-L1),which determines the clinical therapeutic efficacy of MSCs for inflammatory or immune diseases.In MSCs,interferon-gamma(IFN-γ)is a key inducer of PD-L1 expression,which is synergistically enhanced by tumor necrosis factor-alpha(TNF-α);however,the underlying mechanism is unclear.AIM To reveal the mechanism of pretreated MSCs express high PD-L1 and explore the application of pretreated MSCs in ulcerative colitis.METHODS We assessed PD-L1 expression in human umbilical-cord-derived MSCs(hUC-MSCs)induced by IFN-γand TNF-α,alone or in combination.Additionally,we performed signal pathway inhibitor experiments as well as RNA interference experiments to elucidate the molecular mechanism by which IFN-γalone or in combination with TNF-αinduces PD-L1 expression.Moreover,we used luciferase reporter gene experiments to verify the binding sites of the transcription factors of each signal transduction pathway to the targeted gene promoters.Finally,we evaluated the immunosuppressive capacity of hUC-MSCs treated with IFN-γand TNF-αin both an in vitro mixed lymphocyte culture assay,and in vivo in mice with dextran sulfate sodium-induced acute colitis.RESULTS Our results suggest that IFN-γinduction alone upregulates PD-L1 expression in hUC-MSCs while TNF-αalone does not,and that the co-induction of IFN-γand TNF-αpromotes higher expression of PD-L1.IFN-γinduces hUCMSCs to express PD-L1,in which IFN-γactivates the JAK/STAT1 signaling pathway,up-regulates the expression of the interferon regulatory factor 1(IRF1)transcription factor,promotes the binding of IRF1 and the PD-L1 gene promoter,and finally promotes PD-L1 mRNA.Although TNF-αalone did not induce PD-L1 expression in hUCMSCs,the addition of TNF-αsignificantly enhanced IFN-γ-induced JAK/STAT1/IRF1 activation.TNF-αupregulated IFN-γreceptor expression through activation of the nuclear factor kappa-B signaling pathway,which significantly enhanced IFN-γsignaling.Finally,co-induced hUC-MSCs have a stronger inhibitory effect on lymphocyte proliferation,and significantly ameliorate weight loss,mucosal damage,inflammatory cell infiltration,and up-regulation of inflammatory factors in colitis mice.CONCLUSION Overall,our results suggest that IFN-γand TNF-αenhance both the immunosuppressive ability of hUC-MSCs and their efficacy in ulcerative colitis by synergistically inducing high expression of PD-L1.展开更多
BACKGROUND The development of immune checkpoint inhibitors(ICIs)has heralded a new era in cancer treatment,enabling the possibility of long-term survival in patients with metastatic disease.Unfortunately,ICIs are incr...BACKGROUND The development of immune checkpoint inhibitors(ICIs)has heralded a new era in cancer treatment,enabling the possibility of long-term survival in patients with metastatic disease.Unfortunately,ICIs are increasingly implicated in the development of autoimmune diseases.CASE SUMMARY We present a man with squamous cell carcinoma of the oropharynx on a combination of teriprizumab,docetaxel,and cisplatin therapy who developed autoimmune polyendocrine syndrome typeⅡ(APS-2)including thyroiditis and type 1 diabetes mellitus and Crohn’s disease(CD).He developed thirst,abdominal pain,and fatigue after two-week treatment with the protein 1 ligand inhibitor teriprizumab.Biochemistry confirmed APS-2 and thyrotoxicosis.He was commenced on an insulin infusion.However,his abdominal pain persisted.Follow-up surgery confirmed CD and his abdominal pain was relieved by mesalazine.He was continued on insulin and mesalazine therapy.CONCLUSION Immunotherapy can affect all kinds of organs.When clinical symptoms cannot be explained by a single disease,clinicians should consider the possibility of multisystem damage.展开更多
Background:Cancer immunotherapy has emerged as a promising strategy against triple-negative breast cancer(TNBC).One of the immunosuppressive pathways involves programmed cell death-1(PD-1)and programmed cell death lig...Background:Cancer immunotherapy has emerged as a promising strategy against triple-negative breast cancer(TNBC).One of the immunosuppressive pathways involves programmed cell death-1(PD-1)and programmed cell death ligand-1(PD-L1),but many patients derived little benefit from PD-1/PD-L1 checkpoint blockades treatment.Prior research has shown that MYC,a master transcription amplifier highly expressed in TNBC cells,can regulate the tumor immune microenvironment and constrain the efficacy of immunotherapy.This study aims to investigate the regulatory relationship between MYC and PD-L1,and whether a cyclin-dependent kinase(CDK)inhibitor that inhibits MYC expression in combination with anti-PD-L1 antibodies can enhance the response to immunotherapy.Methods:Public databases and TNBC tissue microarrays were used to study the correlation between MYC and PD-L1.The expression of MYC and PD-L1 in TNBCs was examined by quantitative real-time polymerase chain reaction and Western blotting.A patient-derived tumor xenograft(PDTX)model was used to evaluate the influence of a CDK7 inhibitor THZ1 on PD-L1 expression.Cell proliferation and migration were detected by 5-ethynyl-2′-deoxyuridine(EdU)cell proliferation and cell migration assays.Tumor xenograft models were established for in vivo verification.Results:A high MYC expression level was associated with a poor prognosis and could alter the proportion of tumor-infiltrating immune cells(TIICs).The positive correlation between MYC and PD-L1 was confirmed by immunostaining samples from 165 TNBC patients.Suppression of MYC in TNBC caused a reduction in the levels of both PD-L1 messenger RNA and protein.In addition,antitumor immune response was enhanced in the TNBC cancer xenograft mouse model with suppression of MYC by CDK7 inhibitor THZ1.Conclusions:The combined therapy of CDK7 inhibitor THZ1 and anti-PD-L1 antibody appeared to have a synergistic effect,which might offer new insight for enhancing immunotherapy in TNBC.展开更多
BACKGROUND Liver cancer is the sixth most frequently occurring cancer in the world and the fourth most common cause of cancer mortality.The pathogenesis of liver cancer is closely associated with inflammation and immu...BACKGROUND Liver cancer is the sixth most frequently occurring cancer in the world and the fourth most common cause of cancer mortality.The pathogenesis of liver cancer is closely associated with inflammation and immune response in the tumor microenvironment.New therapeutic agents for liver cancer,which can control inflammation and restore cellular immunity,are required.Curcumin(Cur)is a natural anti-inflammatory drug,and total ginsenosides(TG)are a commonly used immunoregulatory drug.Of note,both Cur and TG have been shown to exert anti-liver cancer effects.AIM To determine the synergistic immunomodulatory and anti-inflammatory effects of Cur combined with TG in a mouse model of subcutaneous liver cancer.METHODS A subcutaneous liver cancer model was established in BALB/c mice by a subcutaneous injection of hepatoma cell line.Animals were treated with Cur(200 mg/kg per day),TG(104 mg/kg per day or 520 mg/kg per day),the combination of Cur(200 mg/kg per day)and TG(104 mg/kg per day or 520 mg/kg per day),or 5-fluorouracil combined with cisplatin as a positive control for 21 d.Tumor volume was measured and the protein expression of programmed cell death 1 and programmed cell death 1 ligand 1(PD-L1),inflammatory indicators Toll like receptor 4(TLR4)and nuclear factor-κB(NF-κB),and vascular growth-related factors nitric oxide synthases(iNOS)and matrix metalloproteinase 9 were analyzed by Western blot analysis.CD4+CD25+Foxp3+regulatory T cells(Tregs)were counted by flow cytometry.RESULTS The combination therapy of Cur and TG significantly inhibited the growth of liver cancer,as compared to vehicle-treated animals,and TG showed dose dependence.Cur combined with TG-520 markedly decreased the protein expression of PD-L1(P<0.0001),while CD4+CD25+Foxp3+Tregs regulated by the PD-L1 signaling pathway exhibited a positive correlation with PD-L1.Cur combined with TG-520 also inhibited the cascade action mediated by NF-κB(P<0.0001),thus inhibiting the TLR4/NF-κB signalling pathway(P=0.0088,P<0.0001),which is associated with inflammation and acts on PD-L1.It also inhibited the NF-κB-MMP9 signalling pathway(P<0.0001),which is associated with tumor angiogenesis.CONCLUSION Cur combined with TG regulates immune escape through the PD-L1 pathway and inhibits liver cancer growth through NF-κB-mediated inflammation and angiogenesis.展开更多
Even though immune checkpoint inhibitors(ICIs)are effective on multiple cancer types,there are still many non-responding patients.A possible factor put forward that may influence the efficacy of ICIs is the gut microb...Even though immune checkpoint inhibitors(ICIs)are effective on multiple cancer types,there are still many non-responding patients.A possible factor put forward that may influence the efficacy of ICIs is the gut microbiota.Additionally,faecal microbiota transplantation may enhance efficacy of ICIs.Nevertheless,the data available in this field are insufficient,and relevant scientific work has just commenced.As a result,the current work reviewed the latest research on the association of gut microbiota with ICI treatments based on anti-programmed cell death protein 1 antibody and anti-cytotoxic T-lymphocyte-associated protein 4 antibody and explored the therapeutic potential of faecal microbiota transplantation in combination with ICI therapy in the future.展开更多
BACKGROUND Immune checkpoint inhibitors(ICIs)are a new class of antitumor drugs that have been approved to treat a variety of malignant tumors.However,the occurrence of immune related adverse events(irAEs)has become a...BACKGROUND Immune checkpoint inhibitors(ICIs)are a new class of antitumor drugs that have been approved to treat a variety of malignant tumors.However,the occurrence of immune related adverse events(irAEs)has become an important reason for terminating treatment.ICIs sometimes lead to diarrhea and colitis,with severe enterocolitis potentially causing the hemorrhage of the lower gastrointestinal tract and colonic perforation.ICI-associated colitis is primarily treated with glucorticosteroids and/or agents targeting tumor necrosis factor-α.Here,we describe a case of severe ICI-associated colitis due to anti-programmed cell death ligand 1(PD-L1)(durvalumab)treatment for small cell lung cancer with liver metastasis.The patient exhibited a poor response to rescuable therapy,and eventually received a laparoscopic subtotal colectomy and ileostomy.The data presented here will contribute to optimizing current treatment strategies for patients with severe ICI-associated colitis.CASE SUMMARY A 71-year-old man was admitted for a second course of anti-PD-L1+IP(durvalumab+irinotecan+cisplatin)treatment to manage lung cancer with liver metastasis,diagnosed 1 mo previously.Four days after the second dose,the patient developed abdominal pain and bloody diarrhea.Due to the anti-PD-L1 medication history and colonoscopy findings of the patient,he was diagnosed with a colitis associated with ICI treatment.After treatment with sufficient glucocorticoids and two courses of infliximab,the patient developed severe lower gastrointestinal bleeding.After adequate assessment,the patient was treated by laparoscopic surgery,and was discharged in stable condition.CONCLUSION The early screening and hierarchical management of irAEs need the joint participation of a multidisciplinary team.For ICI-related colitis with ineffective medical treatment,timely surgical intervention could prevent the death of patients.展开更多
BACKGROUND B-cell lymphoma,unclassifiable,with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma(BCLu-DLBCL/cHL),also referred to as gray zone lymphoma(GZL),is known to share f...BACKGROUND B-cell lymphoma,unclassifiable,with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma(BCLu-DLBCL/cHL),also referred to as gray zone lymphoma(GZL),is known to share features with cHL and DLBCL.However,GZL is often difficult to diagnose.There is no consensus regarding the optimal therapeutic regimen.Most reported cases of GZL have been in Caucasian and Hispanic individuals,and its incidence is lower in African-American and Asian populations,including the Japanese population.CASE SUMMARY A 69-year-old female presented at our hospital with a growing mass on the right side of her neck.An elastic,soft mass measuring 9 cm×6 cm was palpable in the right cervical region.Laboratory analyses showed pancytopenia,increased serum lactate dehydrogenase levels,and markedly increased levels of soluble interleukin-2 receptor.Enhanced computed tomography(CT)and fluorodeoxyglucose positron emission tomography(PET)/CT revealed multiple lesions throughout her body.She was diagnosed with GZL based on the characteristic pathological findings,the immunophenotype[CD20+,PAX5+,OCT2+/BOB1(focal+),CD30+,CD15-],and the strong positive expression of neoplastic programmed cell death protein ligand 1(PD-L1)in her lymphoma cells.The lymphoma was stage IV according to the Lugano classification and high-risk according to the International Prognostic Index for aggressive non-Hodgkin lymphoma.The patient received cyclophosphamide,doxorubicin,vincristine,prednisolone,and rituximab(R-CHOP)chemotherapy because the tumor cells were CD20+.She has remained in complete remission for 3 years.CONCLUSION GZL was diagnosed based on histopathology and immunophenotyping with ancillary PD-L1 positivity.R-CHOP chemotherapy was an effective treatment.展开更多
Background:Programmed cell death ligand 1(PD-L1)expression plays an important role in selecting patients with hepatocellular carcinoma who will benefit from anti-programmed cell death 1(PD-1)/PD-L1 monotherapy and dir...Background:Programmed cell death ligand 1(PD-L1)expression plays an important role in selecting patients with hepatocellular carcinoma who will benefit from anti-programmed cell death 1(PD-1)/PD-L1 monotherapy and directing those with lower levels to alternative treatments.Methods:In total,156 hepatocellular carcinoma tumors were stained with three PD-L1 immunohistochemistry assays(SP142,28-8,and E1L3N).Two junior pathologists and one senior pathologist evaluated the pathological slides and recorded the percentages of tumor and immune cells stained at any intensity.Results:Analytical comparisons demonstrated that the anti-PD-L1 assay SP142 is a significantly stronger reagent that stains a higher percent of both tumor and immune cells,while 28-8 and E1L3N behave similarly to each other.The correlation coefficients of the three assays ranged from 0.77 to 0.92 for tumor cells and from 0.66 to 0.75 for immune cells.Next,1%and 5%tumor cell staining cutoffs were designated using various combinations of assays and cutoffs.Across all threereagents,14 samples showedconcordanceabove the5%threshold,eight showed concordancewithinthe range of 1%to 5%interval,and 93 showed concordance below the 1%threshold.The remaining 41 samples showed a combination of discordant results across all three reagents.High PD-L1 expression in tumor and immune cells tended to not be recurrent.Conclusions:The anti-PD-L1 assays 28-8 and E1L3N were closely aligned with regard to staining tumor and immune cells,whereas SP142 showed higher percentages of staining for both cell types.All three assays indicated greater variability in immune cell staining than in tumor cells.展开更多
Esophageal cancer(EC)is one of the most common aggressive malignant tumors in the digestive system with a severe epidemiological situation and poor prognosis.The early diagnostic rate of EC is low,and most EC patients...Esophageal cancer(EC)is one of the most common aggressive malignant tumors in the digestive system with a severe epidemiological situation and poor prognosis.The early diagnostic rate of EC is low,and most EC patients are diagnosed at an advanced stage.Multiple multimodality treatments have gradually evolved into the main treatment for advanced EC,including surgery,chemotherapy,radiotherapy,targeted therapy,and immunotherapy.And the emergence of targeted therapy and immunotherapy has greatly improved the survival of EC patients.This review highlights the latest advances in targeted therapy and immunotherapy for EC,discusses the efficacy and safety of relevant drugs,summarizes related important clinical trials,and tries to provide references for therapeutic strategy of EC.展开更多
Gastric cancer(GC)is one of the most common malignant tumors worldwide.Its incidence ranks the 5th among all malignant tumors globally,and it is the 3rd leading cause of death among patients with cancer.Surgical treat...Gastric cancer(GC)is one of the most common malignant tumors worldwide.Its incidence ranks the 5th among all malignant tumors globally,and it is the 3rd leading cause of death among patients with cancer.Surgical treatment is the first choice in clinical practice.However,targeted therapy,immunotherapy,and other treatment methods have also become research hotspots at home and abroad with the development of individualized precision therapy in recent years,besides traditional radiotherapy and chemotherapy.At present,targeted therapy and immunotherapy are methods used for treating GC,and they have important clinical application value and prospects.This study aimed to review the research progress of targeted therapy and immunotherapy for GC,focusing on its mechanism of action and related important clinical trials,hoping to provide references for the clinical treatment of GC.展开更多
Immune checkpoint blockade(ICB)exhibits considerable benefits in malignancies,but its overall response rate is limited.Previous studies have shown that sphingosine kinases(SPHKs)are critical in the tumor microenvironm...Immune checkpoint blockade(ICB)exhibits considerable benefits in malignancies,but its overall response rate is limited.Previous studies have shown that sphingosine kinases(SPHKs)are critical in the tumor microenvironment(TME),but their role in immunotherapy is unclear.We performed integrative analyses including bioinformatics analysis,functional study,and clinical validation to investigate the role of SPHK1 in tumor immunity.Functionally,we demonstrated that the inhibition of SPHK1 significantly suppressed tumor growth by promoting antitumor immunity in immunocompetent melanoma mouse models and tumor T-cell cocultures.A mechanistic analysis revealed that MTA3 functions as the downstream target of SPHK1 in transcriptionally regulating tumor PD-L1.Preclinically,we found that anti-PD-1 monoclonal antibody(mAb)treatment significantly rescued tumor SPHK1 overexpression or tumor MTA3 overexpression-mediated immune evasion.Significantly,we identified SPHK1 and MTA3 as biological markers for predicting the efficacy of anti-PD-1 mAb therapy in melanoma patients.Our findings revealed a novel role for SPHK1 in tumor evasion mediated by regulating the MTA3-PD-L1 axis,identified SPHK1 and MTA3 as predictors for assessing the efficacy of PD-1 mAb treatment,and provided a therapeutic possibility for the treatment of melanoma patients.展开更多
Inhibitory checkpoint molecules include programmed cell death-1(PD-1),programmed cell death ligand-1(PD-L1),cytotoxic T lymphocyte antigen-4(CTLA-4),human endogenous retrovirus-H Long terminal repeat-associating 2(HHL...Inhibitory checkpoint molecules include programmed cell death-1(PD-1),programmed cell death ligand-1(PD-L1),cytotoxic T lymphocyte antigen-4(CTLA-4),human endogenous retrovirus-H Long terminal repeat-associating 2(HHLA2),B7 homolog 4 protein(B7-H4),T cell membrane protein-3(TIM-3)and Lymphocyte-activation gene 3(LAG-3),which are up-regulated during tumorigenesis.These pathways are essential to down-regulate the immune system by blocking the activation of T cells.In recent years,immune checkpoint blockers(ICBs)against PD-1,PD-L1,CTLA-4 or TIM-3 has made remarkable progress in the clinical application,revolutionizing the treatment of malignant tumors and improving patients’overall survival.However,the efficacy of ICBs in some patients does not seem to be good enough,and more immune-related adverse events(irAEs)will inevitably occur.Therefore,biomarkers research provides practical guidance for clinicians to identify patients who are most likely to benefit from or exhibit resistance to particular types of immune checkpoint therapy.There are two points in general.On the one hand,given the spatial and temporal differential expression of immune checkpoint molecules during immunosuppression process,it is essential to understand their mechanisms to design the most effective individualized therapy.On the other hand,due to the lack of potent immune checkpoints,it is necessary to combine them with novel biomarkers(such as exosomes and ctDNA)and other anticancer modalities(such as chemotherapy and radiotherapy).展开更多
In 2018,the Nobel Prize in medicine was awarded to James P.Allison and Tasuku Honjo for their work on the description of immune checkpoint inhibitors which contributed to the development of new anti-cancer immunothera...In 2018,the Nobel Prize in medicine was awarded to James P.Allison and Tasuku Honjo for their work on the description of immune checkpoint inhibitors which contributed to the development of new anti-cancer immunotherapies.However,although these new therapeutic strategies,which are designed to limit immune escape of cancer cells,have been used or tested successfully in many different cancers,a large proportion of patients have been described to resist and not respond to these new treatments.The new incoming challenge is now therefore to overcome these resistance and new recent data presented epigenetic modifications as promising targets to restore anti-tumor immunity.Indeed,both DNA methylation and post-translational histone modifications have been described to regulate immune checkpoint inhibitor expression,tumor-associated antigen presentation or cancer cell editing by the immune system and therefore establishing epigenetic drugs as a potential complement to immunotherapies to improve their efficiency.展开更多
基金This work was supported by grants from the National Natural Science Foundation of China(Grant Nos.81974416 and 81872166)the Key Project of Tianjin Health Industry(Grant No.15KG145).
文摘The programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)signaling pathway is an important mechanism in tumor immune escape,and expression of PD-L1 on tumor cells has been reported more frequently.However,accumulating evidence suggests that PD-1/PD-L1 is also widely expressed on immune cells,and that regulation is also critical for tumor immune responses.In this review,we emphasized that under solid tumor conditions,the immunoregulatory effects of immune cells expressing PD-1 or PD-L1,affected the prognoses of cancer patients.Therefore,a better understanding of the mechanisms that regulate PD-1 or PD-L1 expression on immune cells would provide clear insights into the increased efficacy of anti-PD antibodies and the development of novel tumor immunotherapy strategies.
基金Supported by The Special Research Foundation of the National Nature Science Foundation of China,No.81972262 and No.81972255The Guangdong Basic and Applied Basic Research Foundation,No.2018A030313645,No.2020A1515010117 and No.2016A030313840+4 种基金Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology,No.[2013]163the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes,No.KLB09001Guangdong Science and Technology Department,No.2015B050501004Guangdong Science and Technology Department,No.2017B030314026Sun Yat-sen University Clinical Research 5010 Program,No.2018008.
文摘BACKGROUND Recurrent hepatocellular carcinoma(HCC)with inferior vena cava tumor thrombus is a great challenge for oncologists and has a poor prognosis.To date,the safety and efficacy of programmed cell death ligand 1(PD-L1)inhibitors are still unknown.CASE SUMMARY A 59-year-old male was identified as having a tumor thrombus in the inferior vena cava 3 years after surgery.The patient underwent a second surgery and adjuvant chemotherapy.However,the level of alpha-fetoprotein was elevated after 2 mo,and lung metastases and mediastinal lymph node metastases were identified.The expression of PD-L1 in HCC and inferior vena cava tumor thrombus tissues was analyzed by immunohistochemistry.Then,the patient received atezolizumab immunotherapy.The level of alpha-fetoprotein dropped to normal,the mediastinal lymph node metastases decreased in size and the lung metastases disappeared after 3 mo of immunotherapy.The patient had no signs of recurrence at 21 mo of follow-up.A 60-year-old male underwent left hepatic tumor resection,inferior vena cava incision and thrombus removal,followed by regular chemotherapy.The patient developed lung and splenic metastases after surgery.Pembrolizumab was used for six courses,and the splenic metastasis shrank,after which splenectomy was performed.The patient continued to receive pembrolizumab for thirteen courses,and the lung metastases showed no progression.A 34-year-old male was diagnosed with liver cancer with inferior vena cava tumor thrombus.The patient underwent right hepatectomy and received tislelizumab for three courses.He is still receiving immunotherapy and in good condition.CONCLUSION Anti-PD-L1 therapy in HCC patients with inferior vena cava tumor thrombus and metastasis is associated with relatively good patient outcomes.
基金Supported by CAMS Innovation Fund for Medical Science(CIFMS),No.CAMS-2016-I2M-3-025Beijing Hope Run Special Fund of Cancer Foundation of China,No.LC2020L05.
文摘In recent years,a number of targeted therapeutic agents have achieved success in phase III trials in patients with advanced hepatocellular carcinoma(HCC),including sorafenib,lenvatinib,and regorafenib.Immunotherapy is considered to be an effective treatment for advanced HCC.Immune checkpoint inhibitors targeting programmed cell death 1(PD-1)/programmed cell death ligand 1(PDL1)are important antitumor immunotherapy agents that represent breakthroughs in the treatment of advanced HCC.However,treating advanced HCC is still a great challenge,and the need for new treatments remains urgent.This review briefly summarizes the research progress in the use of PD-1/PD-L1 inhibitors combined with targeted therapy for treating HCC.
文摘Background:Programmed cell death 1(PD-1)and programmed cell death ligand 1(PD-L1)inhibitors have become integral elements within the current landscape of breast cancer treatment modalities;however,they are associ-ated with interstitial lung disease(ILD),which is rare but potentially fatal.Notably,only a few studies have compared the difference in ILD incidence between PD-1 and PD-L1 inhibitors.Therefore,this study aimed to assess the discrepancies regarding ILD risk between the two immune checkpoint inhibitors.We also reported three cases of ILD after PD-1 inhibitor treatment.Methods:We comprehensively searched PubMed,EMBASE,and the Cochrane Library to identify clinical trials that investigated PD-1/PD-L1 inhibitor treatment for patients with breast cancer.Pooled overall estimates of incidence and risk ratio(RR)were calculated with a 95%confidence interval(CI),and a mirror group analysis was per-formed using eligible studies.Results:This meta-analysis included 29 studies with 4639 patients who received PD-1/PD-L1 inhibitor treatment.A higher ILD incidence was observed among 2508 patients treated with PD-1 inhibitors than among 2131 patients treated with PD-L1 inhibitors(0.05 vs.0.02).The mirror group analysis further revealed a higher ILD event risk in patients treated with PD-1 inhibitors than in those treated with PD-L1 inhibitors(RR=2.34,95%CI,1.13-4.82,P=0.02).Conclusion:Our findings suggest a greater risk of ILD with PD-1 inhibitors than with PD-L1 inhibitors.These findings are instrumental for clinicians in treatment deliberations,and the adoption of more structured diagnostic approaches and management protocols is necessary to mitigate the risk of ILD.
基金Supported by the National Natural Science Foundation of China,No.81871568,No.32100643COVID-19 Infection and Prevention Emergency Special Project of Chongqing Education Commission,No.KYYJ202009.
文摘BACKGROUND The immunosuppressive capacity of mesenchymal stem cells(MSCs)is dependent on the“license”of several proinflammatory factors to express immunosuppressive factors such as programmed cell death 1 ligand 1(PD-L1),which determines the clinical therapeutic efficacy of MSCs for inflammatory or immune diseases.In MSCs,interferon-gamma(IFN-γ)is a key inducer of PD-L1 expression,which is synergistically enhanced by tumor necrosis factor-alpha(TNF-α);however,the underlying mechanism is unclear.AIM To reveal the mechanism of pretreated MSCs express high PD-L1 and explore the application of pretreated MSCs in ulcerative colitis.METHODS We assessed PD-L1 expression in human umbilical-cord-derived MSCs(hUC-MSCs)induced by IFN-γand TNF-α,alone or in combination.Additionally,we performed signal pathway inhibitor experiments as well as RNA interference experiments to elucidate the molecular mechanism by which IFN-γalone or in combination with TNF-αinduces PD-L1 expression.Moreover,we used luciferase reporter gene experiments to verify the binding sites of the transcription factors of each signal transduction pathway to the targeted gene promoters.Finally,we evaluated the immunosuppressive capacity of hUC-MSCs treated with IFN-γand TNF-αin both an in vitro mixed lymphocyte culture assay,and in vivo in mice with dextran sulfate sodium-induced acute colitis.RESULTS Our results suggest that IFN-γinduction alone upregulates PD-L1 expression in hUC-MSCs while TNF-αalone does not,and that the co-induction of IFN-γand TNF-αpromotes higher expression of PD-L1.IFN-γinduces hUCMSCs to express PD-L1,in which IFN-γactivates the JAK/STAT1 signaling pathway,up-regulates the expression of the interferon regulatory factor 1(IRF1)transcription factor,promotes the binding of IRF1 and the PD-L1 gene promoter,and finally promotes PD-L1 mRNA.Although TNF-αalone did not induce PD-L1 expression in hUCMSCs,the addition of TNF-αsignificantly enhanced IFN-γ-induced JAK/STAT1/IRF1 activation.TNF-αupregulated IFN-γreceptor expression through activation of the nuclear factor kappa-B signaling pathway,which significantly enhanced IFN-γsignaling.Finally,co-induced hUC-MSCs have a stronger inhibitory effect on lymphocyte proliferation,and significantly ameliorate weight loss,mucosal damage,inflammatory cell infiltration,and up-regulation of inflammatory factors in colitis mice.CONCLUSION Overall,our results suggest that IFN-γand TNF-αenhance both the immunosuppressive ability of hUC-MSCs and their efficacy in ulcerative colitis by synergistically inducing high expression of PD-L1.
文摘BACKGROUND The development of immune checkpoint inhibitors(ICIs)has heralded a new era in cancer treatment,enabling the possibility of long-term survival in patients with metastatic disease.Unfortunately,ICIs are increasingly implicated in the development of autoimmune diseases.CASE SUMMARY We present a man with squamous cell carcinoma of the oropharynx on a combination of teriprizumab,docetaxel,and cisplatin therapy who developed autoimmune polyendocrine syndrome typeⅡ(APS-2)including thyroiditis and type 1 diabetes mellitus and Crohn’s disease(CD).He developed thirst,abdominal pain,and fatigue after two-week treatment with the protein 1 ligand inhibitor teriprizumab.Biochemistry confirmed APS-2 and thyrotoxicosis.He was commenced on an insulin infusion.However,his abdominal pain persisted.Follow-up surgery confirmed CD and his abdominal pain was relieved by mesalazine.He was continued on insulin and mesalazine therapy.CONCLUSION Immunotherapy can affect all kinds of organs.When clinical symptoms cannot be explained by a single disease,clinicians should consider the possibility of multisystem damage.
基金Key International Cooperation of the National Natural Science Foundation of China(No. 81920108029)Key Foundation for Social Development Project of the Jiangsu Province, China(No. BE2021741)
文摘Background:Cancer immunotherapy has emerged as a promising strategy against triple-negative breast cancer(TNBC).One of the immunosuppressive pathways involves programmed cell death-1(PD-1)and programmed cell death ligand-1(PD-L1),but many patients derived little benefit from PD-1/PD-L1 checkpoint blockades treatment.Prior research has shown that MYC,a master transcription amplifier highly expressed in TNBC cells,can regulate the tumor immune microenvironment and constrain the efficacy of immunotherapy.This study aims to investigate the regulatory relationship between MYC and PD-L1,and whether a cyclin-dependent kinase(CDK)inhibitor that inhibits MYC expression in combination with anti-PD-L1 antibodies can enhance the response to immunotherapy.Methods:Public databases and TNBC tissue microarrays were used to study the correlation between MYC and PD-L1.The expression of MYC and PD-L1 in TNBCs was examined by quantitative real-time polymerase chain reaction and Western blotting.A patient-derived tumor xenograft(PDTX)model was used to evaluate the influence of a CDK7 inhibitor THZ1 on PD-L1 expression.Cell proliferation and migration were detected by 5-ethynyl-2′-deoxyuridine(EdU)cell proliferation and cell migration assays.Tumor xenograft models were established for in vivo verification.Results:A high MYC expression level was associated with a poor prognosis and could alter the proportion of tumor-infiltrating immune cells(TIICs).The positive correlation between MYC and PD-L1 was confirmed by immunostaining samples from 165 TNBC patients.Suppression of MYC in TNBC caused a reduction in the levels of both PD-L1 messenger RNA and protein.In addition,antitumor immune response was enhanced in the TNBC cancer xenograft mouse model with suppression of MYC by CDK7 inhibitor THZ1.Conclusions:The combined therapy of CDK7 inhibitor THZ1 and anti-PD-L1 antibody appeared to have a synergistic effect,which might offer new insight for enhancing immunotherapy in TNBC.
基金the National Natural Science Foundation of China,No.81473617the Science and Technology Department of Hunan Province,No.2017SK50310the Hunan Education Department’s Science and Research Project,No.16K066.
文摘BACKGROUND Liver cancer is the sixth most frequently occurring cancer in the world and the fourth most common cause of cancer mortality.The pathogenesis of liver cancer is closely associated with inflammation and immune response in the tumor microenvironment.New therapeutic agents for liver cancer,which can control inflammation and restore cellular immunity,are required.Curcumin(Cur)is a natural anti-inflammatory drug,and total ginsenosides(TG)are a commonly used immunoregulatory drug.Of note,both Cur and TG have been shown to exert anti-liver cancer effects.AIM To determine the synergistic immunomodulatory and anti-inflammatory effects of Cur combined with TG in a mouse model of subcutaneous liver cancer.METHODS A subcutaneous liver cancer model was established in BALB/c mice by a subcutaneous injection of hepatoma cell line.Animals were treated with Cur(200 mg/kg per day),TG(104 mg/kg per day or 520 mg/kg per day),the combination of Cur(200 mg/kg per day)and TG(104 mg/kg per day or 520 mg/kg per day),or 5-fluorouracil combined with cisplatin as a positive control for 21 d.Tumor volume was measured and the protein expression of programmed cell death 1 and programmed cell death 1 ligand 1(PD-L1),inflammatory indicators Toll like receptor 4(TLR4)and nuclear factor-κB(NF-κB),and vascular growth-related factors nitric oxide synthases(iNOS)and matrix metalloproteinase 9 were analyzed by Western blot analysis.CD4+CD25+Foxp3+regulatory T cells(Tregs)were counted by flow cytometry.RESULTS The combination therapy of Cur and TG significantly inhibited the growth of liver cancer,as compared to vehicle-treated animals,and TG showed dose dependence.Cur combined with TG-520 markedly decreased the protein expression of PD-L1(P<0.0001),while CD4+CD25+Foxp3+Tregs regulated by the PD-L1 signaling pathway exhibited a positive correlation with PD-L1.Cur combined with TG-520 also inhibited the cascade action mediated by NF-κB(P<0.0001),thus inhibiting the TLR4/NF-κB signalling pathway(P=0.0088,P<0.0001),which is associated with inflammation and acts on PD-L1.It also inhibited the NF-κB-MMP9 signalling pathway(P<0.0001),which is associated with tumor angiogenesis.CONCLUSION Cur combined with TG regulates immune escape through the PD-L1 pathway and inhibits liver cancer growth through NF-κB-mediated inflammation and angiogenesis.
基金Science Research Start-up Fund for Doctor of Shanxi Medical University,No.XD1807Science Research Start-up Fund for Doctor of Shanxi Province,No.SD1807+1 种基金Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi,No.2019L0425Shanxi Province Science Foundation for Youths,No.201901D211314.
文摘Even though immune checkpoint inhibitors(ICIs)are effective on multiple cancer types,there are still many non-responding patients.A possible factor put forward that may influence the efficacy of ICIs is the gut microbiota.Additionally,faecal microbiota transplantation may enhance efficacy of ICIs.Nevertheless,the data available in this field are insufficient,and relevant scientific work has just commenced.As a result,the current work reviewed the latest research on the association of gut microbiota with ICI treatments based on anti-programmed cell death protein 1 antibody and anti-cytotoxic T-lymphocyte-associated protein 4 antibody and explored the therapeutic potential of faecal microbiota transplantation in combination with ICI therapy in the future.
基金Shanghai Municipal Health Commission,Shanghai Municipal Administrator of Traditional Chinese Medicine,No.ZY(2021-2023)-0201-02.
文摘BACKGROUND Immune checkpoint inhibitors(ICIs)are a new class of antitumor drugs that have been approved to treat a variety of malignant tumors.However,the occurrence of immune related adverse events(irAEs)has become an important reason for terminating treatment.ICIs sometimes lead to diarrhea and colitis,with severe enterocolitis potentially causing the hemorrhage of the lower gastrointestinal tract and colonic perforation.ICI-associated colitis is primarily treated with glucorticosteroids and/or agents targeting tumor necrosis factor-α.Here,we describe a case of severe ICI-associated colitis due to anti-programmed cell death ligand 1(PD-L1)(durvalumab)treatment for small cell lung cancer with liver metastasis.The patient exhibited a poor response to rescuable therapy,and eventually received a laparoscopic subtotal colectomy and ileostomy.The data presented here will contribute to optimizing current treatment strategies for patients with severe ICI-associated colitis.CASE SUMMARY A 71-year-old man was admitted for a second course of anti-PD-L1+IP(durvalumab+irinotecan+cisplatin)treatment to manage lung cancer with liver metastasis,diagnosed 1 mo previously.Four days after the second dose,the patient developed abdominal pain and bloody diarrhea.Due to the anti-PD-L1 medication history and colonoscopy findings of the patient,he was diagnosed with a colitis associated with ICI treatment.After treatment with sufficient glucocorticoids and two courses of infliximab,the patient developed severe lower gastrointestinal bleeding.After adequate assessment,the patient was treated by laparoscopic surgery,and was discharged in stable condition.CONCLUSION The early screening and hierarchical management of irAEs need the joint participation of a multidisciplinary team.For ICI-related colitis with ineffective medical treatment,timely surgical intervention could prevent the death of patients.
文摘BACKGROUND B-cell lymphoma,unclassifiable,with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma(BCLu-DLBCL/cHL),also referred to as gray zone lymphoma(GZL),is known to share features with cHL and DLBCL.However,GZL is often difficult to diagnose.There is no consensus regarding the optimal therapeutic regimen.Most reported cases of GZL have been in Caucasian and Hispanic individuals,and its incidence is lower in African-American and Asian populations,including the Japanese population.CASE SUMMARY A 69-year-old female presented at our hospital with a growing mass on the right side of her neck.An elastic,soft mass measuring 9 cm×6 cm was palpable in the right cervical region.Laboratory analyses showed pancytopenia,increased serum lactate dehydrogenase levels,and markedly increased levels of soluble interleukin-2 receptor.Enhanced computed tomography(CT)and fluorodeoxyglucose positron emission tomography(PET)/CT revealed multiple lesions throughout her body.She was diagnosed with GZL based on the characteristic pathological findings,the immunophenotype[CD20+,PAX5+,OCT2+/BOB1(focal+),CD30+,CD15-],and the strong positive expression of neoplastic programmed cell death protein ligand 1(PD-L1)in her lymphoma cells.The lymphoma was stage IV according to the Lugano classification and high-risk according to the International Prognostic Index for aggressive non-Hodgkin lymphoma.The patient received cyclophosphamide,doxorubicin,vincristine,prednisolone,and rituximab(R-CHOP)chemotherapy because the tumor cells were CD20+.She has remained in complete remission for 3 years.CONCLUSION GZL was diagnosed based on histopathology and immunophenotyping with ancillary PD-L1 positivity.R-CHOP chemotherapy was an effective treatment.
文摘Background:Programmed cell death ligand 1(PD-L1)expression plays an important role in selecting patients with hepatocellular carcinoma who will benefit from anti-programmed cell death 1(PD-1)/PD-L1 monotherapy and directing those with lower levels to alternative treatments.Methods:In total,156 hepatocellular carcinoma tumors were stained with three PD-L1 immunohistochemistry assays(SP142,28-8,and E1L3N).Two junior pathologists and one senior pathologist evaluated the pathological slides and recorded the percentages of tumor and immune cells stained at any intensity.Results:Analytical comparisons demonstrated that the anti-PD-L1 assay SP142 is a significantly stronger reagent that stains a higher percent of both tumor and immune cells,while 28-8 and E1L3N behave similarly to each other.The correlation coefficients of the three assays ranged from 0.77 to 0.92 for tumor cells and from 0.66 to 0.75 for immune cells.Next,1%and 5%tumor cell staining cutoffs were designated using various combinations of assays and cutoffs.Across all threereagents,14 samples showedconcordanceabove the5%threshold,eight showed concordancewithinthe range of 1%to 5%interval,and 93 showed concordance below the 1%threshold.The remaining 41 samples showed a combination of discordant results across all three reagents.High PD-L1 expression in tumor and immune cells tended to not be recurrent.Conclusions:The anti-PD-L1 assays 28-8 and E1L3N were closely aligned with regard to staining tumor and immune cells,whereas SP142 showed higher percentages of staining for both cell types.All three assays indicated greater variability in immune cell staining than in tumor cells.
基金supported by grants from the National Natural Science Foundation of China(No.82002619)the Key Medical Research Projects of Shanxi Province(No.2020XM55)+2 种基金the Talent Introduction Scientific Research Start-up Fund of Shanxi Bethune Hospital(No.2020RC006)the special fund for Science and Technology Innovation Teams of Shanxi Province(No.202204051001031)Fundamental Research Program of Shanxi Province(No.202203021222349)
文摘Esophageal cancer(EC)is one of the most common aggressive malignant tumors in the digestive system with a severe epidemiological situation and poor prognosis.The early diagnostic rate of EC is low,and most EC patients are diagnosed at an advanced stage.Multiple multimodality treatments have gradually evolved into the main treatment for advanced EC,including surgery,chemotherapy,radiotherapy,targeted therapy,and immunotherapy.And the emergence of targeted therapy and immunotherapy has greatly improved the survival of EC patients.This review highlights the latest advances in targeted therapy and immunotherapy for EC,discusses the efficacy and safety of relevant drugs,summarizes related important clinical trials,and tries to provide references for therapeutic strategy of EC.
基金National Natural Science Foundation of China(No. 82002619)Key Medical Research Projects of Shanxi Province(No. 2020XM55)Talent Introduction Scientific Research Start-up Fund of Shanxi Bethune Hospital(No. 2020RC006)
文摘Gastric cancer(GC)is one of the most common malignant tumors worldwide.Its incidence ranks the 5th among all malignant tumors globally,and it is the 3rd leading cause of death among patients with cancer.Surgical treatment is the first choice in clinical practice.However,targeted therapy,immunotherapy,and other treatment methods have also become research hotspots at home and abroad with the development of individualized precision therapy in recent years,besides traditional radiotherapy and chemotherapy.At present,targeted therapy and immunotherapy are methods used for treating GC,and they have important clinical application value and prospects.This study aimed to review the research progress of targeted therapy and immunotherapy for GC,focusing on its mechanism of action and related important clinical trials,hoping to provide references for the clinical treatment of GC.
基金This work was supported by the National Key Research and Development Program of China(No.2019YFA0111600,No.2019YFE0120800)the Natural Science Foundation of China for Outstanding Young Scholars(No.82022060)+3 种基金the National Natural Science Foundation of China(No.81874242,No.31800979,No.62102455)the Natural Science Foundation of Hunan Province for Outstanding Young Scholars(No.2019JJ30040)China Postdoctoral Science Foundation(No.2020M682587)Hunan Outstanding Postdoctoral Innovative Talents Program(No.2021RC2035).
文摘Immune checkpoint blockade(ICB)exhibits considerable benefits in malignancies,but its overall response rate is limited.Previous studies have shown that sphingosine kinases(SPHKs)are critical in the tumor microenvironment(TME),but their role in immunotherapy is unclear.We performed integrative analyses including bioinformatics analysis,functional study,and clinical validation to investigate the role of SPHK1 in tumor immunity.Functionally,we demonstrated that the inhibition of SPHK1 significantly suppressed tumor growth by promoting antitumor immunity in immunocompetent melanoma mouse models and tumor T-cell cocultures.A mechanistic analysis revealed that MTA3 functions as the downstream target of SPHK1 in transcriptionally regulating tumor PD-L1.Preclinically,we found that anti-PD-1 monoclonal antibody(mAb)treatment significantly rescued tumor SPHK1 overexpression or tumor MTA3 overexpression-mediated immune evasion.Significantly,we identified SPHK1 and MTA3 as biological markers for predicting the efficacy of anti-PD-1 mAb therapy in melanoma patients.Our findings revealed a novel role for SPHK1 in tumor evasion mediated by regulating the MTA3-PD-L1 axis,identified SPHK1 and MTA3 as predictors for assessing the efficacy of PD-1 mAb treatment,and provided a therapeutic possibility for the treatment of melanoma patients.
基金the National Natural Science Foundation of China(81872200,31900558)the Natural Science Foundation of Hubei Province(2018CFB510)+1 种基金the Zhongnan Hospital of Wuhan University Science,Technology and Innovation Seed Fund(CXPY2017029)the Fundamental Research Funds for the Central Universities(2042018kf0091).
文摘Inhibitory checkpoint molecules include programmed cell death-1(PD-1),programmed cell death ligand-1(PD-L1),cytotoxic T lymphocyte antigen-4(CTLA-4),human endogenous retrovirus-H Long terminal repeat-associating 2(HHLA2),B7 homolog 4 protein(B7-H4),T cell membrane protein-3(TIM-3)and Lymphocyte-activation gene 3(LAG-3),which are up-regulated during tumorigenesis.These pathways are essential to down-regulate the immune system by blocking the activation of T cells.In recent years,immune checkpoint blockers(ICBs)against PD-1,PD-L1,CTLA-4 or TIM-3 has made remarkable progress in the clinical application,revolutionizing the treatment of malignant tumors and improving patients’overall survival.However,the efficacy of ICBs in some patients does not seem to be good enough,and more immune-related adverse events(irAEs)will inevitably occur.Therefore,biomarkers research provides practical guidance for clinicians to identify patients who are most likely to benefit from or exhibit resistance to particular types of immune checkpoint therapy.There are two points in general.On the one hand,given the spatial and temporal differential expression of immune checkpoint molecules during immunosuppression process,it is essential to understand their mechanisms to design the most effective individualized therapy.On the other hand,due to the lack of potent immune checkpoints,it is necessary to combine them with novel biomarkers(such as exosomes and ctDNA)and other anticancer modalities(such as chemotherapy and radiotherapy).
基金This work was supported by funding from institutional grants from INSERM,EFS,and University of Bourgogne Franche-Comtéand by the“Ligue Contre le Cancer”(2017)and the“Région Bourgogne Franche-Comté”(2014C-15449).
文摘In 2018,the Nobel Prize in medicine was awarded to James P.Allison and Tasuku Honjo for their work on the description of immune checkpoint inhibitors which contributed to the development of new anti-cancer immunotherapies.However,although these new therapeutic strategies,which are designed to limit immune escape of cancer cells,have been used or tested successfully in many different cancers,a large proportion of patients have been described to resist and not respond to these new treatments.The new incoming challenge is now therefore to overcome these resistance and new recent data presented epigenetic modifications as promising targets to restore anti-tumor immunity.Indeed,both DNA methylation and post-translational histone modifications have been described to regulate immune checkpoint inhibitor expression,tumor-associated antigen presentation or cancer cell editing by the immune system and therefore establishing epigenetic drugs as a potential complement to immunotherapies to improve their efficiency.
