Tumor-intrinsic signaling pathways key roles i.pdf

REVIEWOpen AccessTumor-intrinsic signaling pathways:key roles in the regulation of theimmunosuppressive tumormicroenvironmentLi Yang1,2,4,Aitian Li1,2,4,Qingyang Lei1,2,4and Yi Zhang1,2,3,4*AbstractImmunotherapy is a currently popular treatment strategy for cancer patients.Although recent developments incancer immunotherapy have had significant clinical impact,only a subset of patients exhibits clinical response.Therefore,understanding the molecular mechanisms of immunotherapy resistance is necessary.The mechanismsof immune escape appear to consist of two distinct tumor characteristics:a decrease in effective immunocyteinfiltration and function and the accumulation of immunosuppressive cells in the tumor microenvironment.Severalhost-derived factors may also contribute to immune escape.Moreover,inter-patient heterogeneity predominantlyresults from differences in somatic mutations between cancers,which has led to the hypothesis that differentialactivation of specific tumor-intrinsic pathways may explain the phenomenon of immune exclusion in a subset ofcancers.Increasing evidence has also shown that tumor-intrinsic signaling plays a key role in regulating theimmunosuppressive tumor microenvironment and tumor immune escape.Therefore,understanding themechanisms underlying immune avoidance mediated by tumor-intrinsic signaling may help identify newtherapeutic targets for expanding the efficacy of cancer immunotherapies.Keywords:Immunosuppressive tumor microenvironment,Immune escape,T cell infiltration,Immunosuppressivecells,Tumor-intrinsic signalingBackgroundThe recent developments in cancer immunotherapyshow significant clinical impact.Particularly,monoclonalantibodies targeting the immune checkpoints cytotoxicT-lymphocyte-associatedprotein4(CTLA-4)andprogrammed cell death protein 1(PD-1)have showndramatic efficacy and have been approved by the FDAfor cancer treatment 14.Nevertheless,only a subsetof patients experiences clinical benefit.Furthermore,chimeric antigen receptor-T(CAR-T)cell therapy hasbeenapprovedforthetreatmentofcertainhematological malignancies,yet solid cancers are oftenless susceptible to CAR-T cell therapy mostly due to theimmunosuppressive tumor microenvironment 5,6.Therefore,understanding the molecular mechanisms ofimmunotherapy resistance,specifically those induced bythe tumor microenvironment,is necessary.The tumor microenvironment consists of the non-cancerous cells present in the tumor,which includesimmune cells,fibroblasts,and cells that comprise theblood vessels 7,8.It has been shown that a subset ofmelanoma patients with metastases exhibits a T cell-inflamed tumor microenvironment as evidenced by geneexpression profiling 9.The T cell-inflamed phenotypealso shows activated immune-inhibitory pathways as wellas expression of PD-L1 and indoleamine-2,3-dioxygenase(IDO)10.In contrast,the lack of T cell infiltration inthe tumor microenvironment appears to avoid antitu-mor immunity through the exclusion of T cells fromthe tumor site.In addition,immunosuppressive cells,The Author(s).2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License(http:/creativecommons.org/licenses/by/4.0/),which permits unrestricted use,distribution,andreproduction in any medium,provided you give appropriate credit to the original author(s)and the source,provide a link tothe Creative Commons license,and indicate if changes were made.The Creative Commons Public Domain Dedication waiver(http:/creativecommons.org/publicdomain/zero/1.0/)applies to the data made available in this article,unless otherwise stated.*Correspondence:1Biotherapy Center,The First Affiliated Hospital of Zhengzhou University,Zhengzhou,Henan 450052,Peoples Republic of China2Cancer Center,The First Affiliated Hospital of Zhengzhou University,Zhengzhou,Henan 450052,Peoples Republic of ChinaFull list of author information is available at the end of the articleYang et al.Journal of Hematology&Oncology (2019)12:125 https:/doi.org/10.1186/s13045-019-0804-8includingtumor-associatedmacrophages(TAMs),myeloid-derived suppressor cells(MDSCs),T regulatorycells(Tregs),and tumor-associated neutrophils(TANs),are also responsible for an immunosuppressive tumormicroenvironment and tumor immune escape 7,1113.Thus,the mechanisms of immune escape appear to bedistinct in two major subsets of tumors,that is,a decreasein effective immunocyte infiltration and function and anincreaseinimmunosuppressivecellsinthetumormicroenvironment.Several host-derived factors may also contribute toimmune escape.Inter-patient heterogeneity predominantlyresults from differences in somatic mutations between can-cers 14,which has led to the hypothesis that differentialactivation of specific tumor-intrinsic pathways may explainthe phenomenon of immune exclusion in a subset of can-cers.In addition to the activation of tumor-intrinsicpathways within the tumor cells themselves,exposure tochronic viral infections,the composition of the intestinalmicrobiota of patients,and the accumulation of germlinepolymorphisms in immune regulatory genes may alsoinfluence the antitumor immunotherapy response 15,16.Tumor-intrinsic signaling pathways are considered tobe oncogenic pathways.Increasing evidence has shownthat tumor-intrinsic signaling plays a key role in regulatingthe immunosuppressive tumor microenvironment andtumor immune escape 17,18.Successful identificationof these pathways would lead to new therapeutic strategiesthat can enable immunocyte entry into non-inflamedtumors and attenuate the immunosuppressive microenvir-onment to increase the number of patients capable ofresponding to immunotherapies.In this review,we willdescribe the mechanisms by which tumor-intrinsic signal-ing pathways regulate the immunosuppressive tumormicroenvironment,including the decrease in effectiveimmunocyte infiltration and function and the accumula-tion of immunosuppressive cells in the tumor microenvir-onment,which may help identify new therapeutic targetsfor enhancing the efficacy of cancer immunotherapy.Effective immunocyte exclusion and dysfunctionThe innate and adaptive immune cells in the tumormicroenvironment harbor both tumor-promoting andtumor-suppressing activities,which may predict cli-nical outcome 19,20.It has been shown that onco-genic drivers of tumors may function to limit hostimmunity in the remaining non-immunocyte inflamedtumors or dysfunction of immunocytes in the tumormicroenvironment,thereby leading to immunoresis-tance(Fig.1,Table 1).Fig.1 Tumor-intrinsic signaling induces the exclusion and dysfunction of effective immunocytes.Oncogenic drivers of tumors,including-catenin,STAT3,PI3K/PTEN/AKT/mTOR,p53,NF-B,and RAS/RAF/MAPK signaling,are activated in the tumor microenvironment.These oncogenicsignaling pathways not only downregulate the production of chemokines,which further decrease the recruitment of DCs,macrophages,T cells,and NK cells to tumor sites,but also induce immunosuppression of these immunocytes.In addition,tumor-intrinsic signaling can induce PD-L1expression in tumor cells,leading to T cell dysfunction in the tumor microenvironmentYang et al.Journal of Hematology&Oncology (2019)12:125 Page 2 of 14Table 1 The influence of different tumor-intrinsic signaling pathways in different cancersSubtypeSignalingTumor typeEffectRefEffective immunocyteexclusion and dysfunction-CateninMelanomaDecreased T cell infiltration18,21,22Inhibition of IFN-production by CTLs23Upregulating the expression and activityof IDO by DCs24STAT3Lung cancerInhibition of CCL5 and CXCL10 productionto decrease T cell infiltration25,26,28PI3K/PTEN/AKT/mTORBreast,prostate,and lungcancer,gliomasRegulation of PD-L1 expression to induceT cell dysfunction29,3133Triple-negative breastcancerDecreased T cell infiltration,regulation ofPD-L1 expression30Multiple cancersDecreased the therapeutic efficacy of anE7-specific vaccine or CD8+T cell adoptivetransfer34p53Liver carcinomaIncreased recruitment and activation ofinnate immune cells37,38Triple-negative breastcancerRegulation of T cell infiltration39NF-BEpithelial ovarian cancerImmunosuppression of DCs andmacrophages42Colitis-associated cancer,cervical cancer,etc.Increased T cell infiltration and activation4346RAS/RAF/MAPKLung adenocarcinoma,RAS mutant cancerInducing PD-L1 expression47,48MelanomaSuppression of DC function50,51MelanomaInhibiting the recognition of tumor cellantigens by tumor-infiltrated T lymphocytes52MelanomaSuppression of proliferation and function ofspecific cytotoxic T cells53GBE1Lung adenocarcinomaDecreased T cell infiltration54KRAS/MYCKRAS-mutant tumorExclusion of B,T,and NK cells55EGFRNon-small cell lung cancer,head and neck cancerUpregulation of PD-L1 expression5660VEGFRChronic myeloid leukemiaInhibited NK cell-mediated immunosurveillance61Recruitment anddifferentiation ofimmunosuppressive cellsPI3K/PTEN/AKTBreast,pancreatic,and lungcarcinomasRecruitment of macrophages and polarizationof TAMs7072SarcomasEnhanced infiltrating myeloid-derivedhematopoietic cells73Prostate cancerIncreased expansion andinfiltration of MDSCs74,75RAS/RAF/MAPKKRAS-driven lungtumorigenesis,melanomaIncreased Treg infiltration76,78BRAFi-resistant melanomaIncreased MDSC infiltration77KRASKRAS-driven non-smallcell lung cancerAccumulation of TANs79KRAS-mutant tumorRecruitment of proangiogenic macrophages55CCRK/mTORObesity-associatedhepatocellular carcinomaRecruitment of MDSCs80RAGEPancreatic carcinogenesisAccumulation of MDSCs81TLR9Prostate cancerExpansion and activation of G-MDSCs82p53 loss-of-functionLate stage metastaticcastration resistant prostatecancerAccumulation of MDSCs83Yang et al.Journal of Hematology&Oncology (2019)12:125 Page 3 of 14-Catenin signalingDifferential activation of the-catenin oncogene path-way within tumor cells themselves contributes to the ro-bustness of a spontaneous antitumor immune response(Fig.1,Table 1).Recently,Spranger et al.21 found that48%of the non-T cell-inflamed tumors show evidence ofWNT/-catenin signaling pathway activation based ongene expression profiling of six defined-catenin targetgenes.In vivo experiments demonstrated that activationof the-catenin pathway within melanoma tumor cellscan dominantly exclude immune cell activation andresult in a non-T cell-inflamed tumor microenviron-ment.-Catenin-mediated immune escape occurs viainhibition of the production of CCL4 derived fromtumor cells;this results from induction of the transcrip-tionalrepressorATF3,whichblocksCCL4genetranscription.The lack of CCL4 secretion results indecreased recruitment of CD103+dendritic cells(DCs),thereby preventing cross-priming of antitumor T cells18,22.In addition,-catenin-overexpressed melano-mas inhibit the production of IFN-by melanoma-specific cytotoxic lymphocytes(CTLs)in an interleukin(IL)-10-independent manner and were more resistant toCTLlysisinvitroandinvivo23.Moreover,melanoma-derived Wnt5a ligand upregulates the durableexpression and activity of IDO enzyme by local DCs in a-catenin signaling pathway-dependent manner 24.STAT3 signalingOne potential candidate for oncogenic drivers leading toimmunoresistance is activation of the STAT3 signalingpathway(Fig.1,Table 1).Constitutively active STAT3signaling in transplantable tumor cell lines has beenreported to decrease expression of proinflammatory me-diators,while expression of a dominant negative STAT3variant resulted in augmented expression of proinflam-matory factors,including the chemokines CCL5 andCXCL10,which are functionally responsible for T cellrecruitment 25,26.Recent studies have provided add-itional evidence for this phenomenon via a carcinogen-induced lung cancer model and a genetically-inducedprostate cancer model 27,28.Using a conditionalknockout model for STAT3,Ihara et al.28 found anincreased antitumor immune response in the absence ofSTAT3 signaling,which was closely associated with in-creased expression of CCL5 and CXCL10;this pheno-type was associated with increased T cell infiltration andfunction within the tumor microenvironment.Thus,theSTAT3 signaling pathway may represent a viable mech-anistic pathway for diminishing immune cell recruitmentinto tumor sites,and based on the currently availabledata,it may interfere with T cell recruitment.PI3K/PTEN/AKT/mTOR signalingThe PI3K/PTEN/AKT/mTOR pathway is another inter-esting candidate that may impact the host immuneresponse(Fig.1,Table 1).The expression of PD-L1,apivotal negative regulator of T cell function,is associatedwith the activation of PI3K in breast and prostate cancerpatients 29.Recent findings have demonstrated thatthe expression of tumor suppressor PTEN was closelyassociated with the lack of T cell infiltration as well aslow PD-L1 expression in the tumor microenvironmentof triple-negative breast cancer 30,indicating that lossof PTEN expression(and constitutive PI3K activation)isassociated with the presence of T cells in the tumormicroenvironment.In the LKB1,PTEN-null model,tumor-propagating cells of human lung squamous cellcarcinoma highly expressed PD-L1,suggesting a mech-anism of immune escape for tumor-propagating cells31.Moreover,loss of PTEN function increases PD-L1expressionandimmunoresistanceingliomas32.Furthermore,oncogenic activation of the AKT-mTORsignaling pathway promotes immune escape by drivingthe expression of PD-L1,which was confirmed insyngeneic and genetically engineered mouse models oflung cancer where combination therapy of an mTORinhibitor with a PD-1 antibody decreased tumor growthand increased T cell infiltration 33.Intratumoral injec-tion of an AKT inhibitor also enhanced the therapeuticefficacy of an E7-specific vaccine or E7-specific CD8+Tcell adoptive transfer against immune-resistant tumors34.These findings indicate that activation of the PI3K/AKT signaling pathway represents a new mechanism ofTable 1 The influence of different tumor-intrinsic signaling pathways in different cancers(Continued)SubtypeSignalingTumor typeEffectRefIDOAdvanced cancerGeneration and activation of MDSCs andTregs64CD200/CD200RChemical skincarcinogenesisInfluencing the ratio of Treg/Th17 cells84,85STAT3Hematopoietic systemRecruiting and promoting the proliferationof Tregs86,87COX2Wilms tumorIncreased Treg infiltration90c-METMelanomaIncreased TAN infiltration91Yang et al.Journal of Hematology&Oncology (2019)12:125 Page 4 of 14immune escape that has important implications for thedevelopment of a novel cancer immunotherapy strategyagainst immune-resistant tumors.p53 signalingMutant p53 is another molecular aberration in cancercells that is associated with immune response(Fig.1,Table 1).Activating/reactivating p53 signaling in thetumor microenvironment represents a compelling im-munological strategy for enhancing antitumor immunityand reversing immunosuppression 35,36.It has beenshown that an intact p53 signaling pathway is correlatedwith increased recruitment and activation of innate im-mune cells 37.In a related study,where cellular senes-cence is triggered in vivo by inducible p5