The heterogeneity of tumor-associated macrophages and strategies to target it

Tumor-associated macrophages(TAMs)are emerging as targets for tumor therapy because of their primary role in promoting tumor progression.Several studies have been conducted to target TAMs by reducing their infiltration,depleting their numbers,and reversing their phenotypes to suppress tumor progression,leading to the development of drugs in preclinical and clinical trials.However,the heterogeneous characteristics of TAMs,including their ontogenetic and functional heterogeneity,limit their targeting.Therefore,in-depth exploration of the heterogeneity of TAMs,combined with immune checkpoint therapy or other therapeutic modalities could improve the efficiency of tumor treatment.This review focuses on the heterogeneous ontogeny and function of TAMs,as well as the current development of tumor therapies targeting TAMs and combination strategies.

Evaluation of 30 DNA damage response and 6 mismatch repair gene mutations as biomarkers for immunotherapy outcomes across multiple solid tumor types

Objective:DNA damage response(DDR)genes have low mutation rates,which may restrict their clinical applications in predicting the outcomes of immune checkpoint inhibitor(ICI)treatment.Thus,a systemic analysis of multiple DDR genes is needed to identify potential biomarkers of ICI efficacy.Methods:A total of 39,631 patients with mutation data were selected from the cBioPortal database.A total of 155 patients with mutation data were obtained from the Fudan University Shanghai Cancer Center(FUSCC).A total of 1,660 patients from the MSK-IMPACT cohort who underwent ICI treatment were selected for survival analysis.A total of 249 patients who underwent ICI treatment from the Dana-Farber Cancer Institute(DFCI)cohort were obtained from a published dataset.The Cancer Genome Atlas(TCGA)level 3 RNA-Seq version 2 RSEM data for gastric cancer were downloaded from cBioPortal.Results:Six MMR and 30 DDR genes were included in this study.Six MMR and 20 DDR gene mutations were found to predict the therapeutic efficacy of ICI,and most of them predicted the therapeutic efficacy of ICI,in a manner dependent on TMB,except for 4 combined DDR gene mutations,which were associated with the therapeutic efficacy of ICI independently of the TMB.Single MMR/DDR genes showed low mutation rates;however,the mutation rate of all the MMR/DDR genes associated with the therapeutic efficacy of ICI was relatively high,reaching 10%–30%in several cancer types.Conclusions:Coanalysis of multiple MMR/DDR mutations aids in selecting patients who are potential candidates for immunotherapy.

Gut microbiota diversity and composition in predicting immunotherapy response and immunotherapy-related colitis in melanoma patients:A systematic review

BACKGROUND Gut microbiome(GM)composition and diversity have recently been studied as a biomarker of response to immune checkpoint blockade therapy(ICB)and of ICBrelated colitis.AIM To conduct a systematic review on the role of GM composition and diversity in predicting response and colitis in patients with melanoma treated with ICB.METHODS The review protocol was registered in PROSPERO:CRD42021228018.From a total of 300 studies,nine studies met inclusion criteria.Two studies were phase I clinical trials,while the remainder were prospective observational studies.All but one study has moderate risk of bias.In addition,we conducted a relevant search by Reference Citation Analysis(RCA)(https://www.referencecitationanalysis.com).RESULTS Fecal samples enriched in Firmicutes phylum were associated with good response to ICB,whereas the Bacteroidales family was associated with poor response to ICB.Samples with greater GM diversity were associated with more favorable response to ICB[hazard ratio(HR)=3.57,95%confidence interval=1.02-12.52,P<0.05].Fecal samples with a higher abundance in Firmicutes were more susceptible to ICB-related colitis(P<0.01)whereas samples enriched in Bacteroidetes were more resistant to ICB-related colitis(P<0.05).Overall,there was limited concordance in the organisms in the GM identified to be associated with response to ICB,and studies evaluating GM diversity showed conflicting results.CONCLUSION This highlights the need for further prospective studies to confirm whether the GM could be used as a biomarker and potential intervention to modulate ICB response in melanoma patients.

Liposome-coated CaO_(2)nanoblockers for enhanced checkpoint blockade therapy by inhibiting PD-L1 de novo biosynthesis

The blocking of the immune checkpoint pathway with antibodies,especially targeting to programmed death-1/programmed death ligand-1(PD-1/PD-L1)pathway,was currently a widely used treatment strategy in clinical practice.However,the shortcomings of PD-L1 antibodies were constantly exposed with the deepening of its research and their therapeutic effect was limited by the translocation and redistribution of intracellular PD-L1.Herein,we proposed to improve immune checkpoint blockade therapy by using liposomes-coated CaO_(2)(CaO_(2)@Lipo)nanoparticles to inhibit the de novo biosynthesis of PD-L1.CaO_(2)@Lipo would produce oxygen and reduce hypoxia-inducible factor-1α(HIF-1α)level,which then downregulated the expression of PD-L1.Our in vitro and in vivo results have confirmed CaO_(2)@Lipo promoted the degradation of HIF-1αand then downregulated the expression of PD-L1 in cancer cells for avoiding immune escape.Furthermore,to mimicking the clinical protocol of anti-PD-L1 antibodies+chemo-drugs,CaO_(2)@Lipo was combined with doxorubicin(DOX)to investigate the tumor inhibition efficiency.We found CaO_(2)@Lipo enhanced DOX-induced immunogenic cell death(ICD)effect,which then promoted the infiltration of T cells,strengthened the blocking effect,thus provided an effective means to overcome the traditional immune checkpoint blockade treatment.

Combining radiation with immune checkpoint inhibitors therapy for HCC: From the alteration of the immune microenvironment by radiotherapy

Hepatocellular carcinoma(HCC),one of the deadliest cancers all over the world,had a limited prognosis in the past.Recently,the remarkable efficacy of immune checkpoint inhibitors(ICIs)therapy has been shown in various solid tumors.What's more,the occurrence of HCC is associated with immune escape and therefore various ICIs have been applied to clinical trials for HCC.However,the special immune environment of the liver creates the complex tumor microenvironment(TME)of HCC,which impairs the overall survival(OS)and overall response rate(OCR)of ICIs as a monotherapy.Lately,various therapies have been used in combination with ICIs therapy to improve its clinical efficacy.Among which,radiotherapy is widely concerned because of its unique immunoreaction.A large number of basic and clinical studies have demonstrated that the combined radiotherapy and ICIs therapy has advantages in improving the OCR and efficacy,as compared with ICIs therapy alone.Herein,this article reviews the studies on the advantages and possible mechanisms of the combination of radiotherapy and ICIs therapy for HCC.

Programmed albumin nanoparticles regulate immunosuppressive pivot to potentiate checkpoint blockade cancer immunotherapy

The therapeutic efficacy of programmed cell death protein 1/programmed cell death-ligand 1(PD-1/PD-L1)blockade immunotherapy is extremely dampened by complex immunosuppressive mechanisms including regulatory T cells(Treg),M2 macrophages(M2),and prostaglandin E2(PGE2).The pivotal roles of PGE2 have been recognized by directly inactivating CD8+T cells and indirectly inducing Treg and M2.Therefore,PGE2 abolishment through inactivating cyclooxygenase-2(COX-2)could be robust to sensitize tumour toward anti-PD-1/PD-L1 immunotherapy,which has gone into clinical trials.However,exploring this promising strategy in nanomedicine to enhance immunotherapy remains unrevealed.The key challenge to synergistically combine COX-2 inhibition and anti-PD-1/PD-L1 lies in the different pharmacokinetic profiles and the spatial obstacles since PD-1/PD-L1 interaction occurs extracellularly and COX-2 locates intracellularly.Thus,the programmed release nanoparticles(termed as Cele-BMS-NPs)are rationally designed,which are composed of pH-sensitive human serum albumin derivative,BMS-202 compound as PD-1/PD-L1 inhibitor,glutathione(GSH)-activatable prodrug of celecoxib(COX-2 inhibitor).The in vitro experiments demonstrate that this smart Cele-BMS-NPs could extracellularly release BMS-202 under the acidic tumour microenvironment,and the intracellularly release of celecoxib in response to the elevated GSH concentration inside tumour cells.After systemic administration,the intratumoral infiltration of CD8+T cells is significantly enhanced and meanwhile immunosuppressive M2,Treg,and PGE2 are reduced,thereby eliciting the anti-tumour immune responses toward low immunogenic tumours and postsurgical tumour recurrences.

Programmed death ligand-1/programmed death-1 inhibition therapy and programmed death ligand-1 expression in urothelial bladder carcinoma

After two decades of unchanged paradigms,the treatment strategies for advanced urothelial bladder cancer have been revolutionized by emerging programmed death ligand-1(PD-Ll)/programmed death-1(PD1)inhibition therapy.Increased evidence is demonstrating the efficacy of PD-L1/PD1 inhibition therapy in both second-line and first-line settings.However,the percentage of patients who benefit from anti-PD-Ll/anti-PDl therapy is still low.Many questions have been raised in the development of biomarkerdriven approaches for disease classification and patient selection.In this perspective,we discuss PD-L1/PD1 expression in urothelial bladder carcinoma,review approved anti-PD-Ll/anti-PDl agents for bladder cancer treatment and current ongoing studies investigating combination treatment strategies,and explore PD-L1 expression status for the evaluation of bladder cancer immunotherapy.

Biomimetic nanoparticles directly remodel immunosuppressive microenvironment for boosting glioblastoma immunotherapy

Glioblastoma(GBM),as a very aggressive cancer of central nervous system,is very challenging to completely cure by the conventional combination of surgical resection with radiotherapy and chemotherapy.The success of emerging immunotherapy in hot tumors has attracted considerable interest for the treatment of GBM,but the unique tumor immunosuppressive microenvironment(TIME)of GBM leads to the failure of immunotherapy.Here,we show the significant improvement of the immunotherapy efficacy of GBM by modulating the TIME through novel all-in-one biomimetic nanoparticles(i.e.CS-I/J@CM NPs).The nanoparticles consist of utrasmall Cu2-xSe nanoparticles(NPs)with outstanding intrinsic properties(e.g.,photo-responsive Fenton-like catalytic property for inducing immunogenic cell death(ICD)and alleviating the hypoxia of tumor),indoximod(IND,an inhibitor of indoleamine-2,3-dioxygenease in tumor),JQ1(an inhibitor for reducing the expression of PD-L1 by tumor cells),and tumor cell membrane for improving the targeting capability and accumulation of nanoparticles in tumor.We reveal that these smart CS-I/J@CM NPs could drastically activate the immune responses through remodeling TIME of GBM by multiple functions.They could(1)increase M1-phenotype macrophages at tumor site by promoting the polarization of tumor-associated macrophages through the reactive oxygen species(ROS)and oxygen generated from the Fenton-like reaction between nanoparticles and H2O2 within tumor under NIR II irradiation;(2)decrease the infiltration of Tregs cells at tumor site through the release of IND;(3)decrease the expression of PD-L1 on tumor cells through JQ1.The notable increments of anti-tumor CD8+T cells in the tumor and memory T cells(TEM)in the spleen show excellent therapy efficacy and effectively prevent the recurrence of GBM after modulation of the TIME.This work demonstrates the modulation of TIME could be a significant strategy to improve the immunotherapy of GBM and other cold tumors.

Immunosuppressive tumor microenvironment in gastric signet-ring cell carcinoma

Gastric signet-ring cell carcinoma(GSRCC)is a subtype of gastric cancer with distinct phenotype and high risk of peritoneal metastasis.Studies have shown that early GSRCC has a good prognosis,while advanced GSRCC is insensitive to radiotherapy,chemotherapy or immune checkpoint blockade therapy.With technological advancement of single-cell RNA sequencing analysis and cytometry by time of flight mass cytometry,more detailed atlas of tumor microenvironment(TME)in GSRCC and its association with prognosis could be investigated extensively.Recently,two single-cell RNA sequencing studies revealed that GSRCC harbored a unique TME,manifested as highly immunosuppressive,leading to high immune escape.The TME of advanced GSRCC was enriched for immunosuppressive factors,including the loss of CXCL13+-cluster of differentiation 8+-Tex cells and declined clonal crosstalk among populations of T and B cells.In addition,GSRCC was mainly infiltrated by follicular B cells.The increased proportion of SRCC was accompanied by a decrease in mucosaassociated lymphoid tissue-derived B cells and a significant increase in follicular B cells,which may be one of the reasons for the poor prognosis of GSRCC.By understanding the relationship between immunosuppressive TME and poor prognosis in GSRCC and the underlying mechanism,more effective immunotherapy strategies and improved treatment outcomes of GSRCC can be anticipated.