1 2660 115 EPITHERAPY AND IMMUNE CHECKPOINT BLOCKADE: USING EPIGENETIC REINVIGORATION OF EXHAUSTED AND DYSFUNCTIONAL T CELLS TO REIMBURSE IMMUNOTHERAPY RESPONSE. BACKGROUND: CANCER CELLS SUBVERT NATURAL IMMUNOSUPPRESSION BY UPREGULATING THE EXPRESSION OF CHECKPOINT PROTEINS AND THEIR LIGANDS. FOR EXAMPLE, TUMOR CELLS EXPRESSING PROGRAMMED DEATH-LIGAND 1 (PD-L1) INDUCE IMMUNE CELL TOLERANCE TO CANCERS, THEREBY FACILITATING TUMOR PROGRESSION. THE RECENT CLINICAL SUCCESS OF IMMUNOTHERAPY, PARTICULARLY CHECKPOINT BLOCKADE, REPRESENTS A SIGNIFICANT ADVANCE IN CANCER THERAPY. HOWEVER, MANY CANCERS DEVELOP RESISTANCE TO IMMUNOTHERAPIES, AND THE UNDERLYING MECHANISMS AND HOW THESE MIGHT BE EXPLOITED TO OVERCOME RESISTANCE STILL NEED TO BE DETERMINED. METHODS: T CELL DYSFUNCTION, IN PART CAUSED BY CHRONIC T CELL RECEPTOR STIMULATION, DIMINISHES THE CAPACITY FOR DURABLE RESPONSES TO CHECKPOINT BLOCKADE. FURTHERMORE, T CELL POPULATIONS ARE PHENOTYPICALLY AND FUNCTIONALLY HETEROGENEOUS, RESULTING IN VARYING RESPONSES TO CHECKPOINT BLOCKADE. RECENT MOLECULAR STUDIES OF T CELL HETEROGENEITY HAVE SHOWN THAT CHECKPOINT BLOCKADE ON ITS OWN DOES NOT ALTER THE EPIGENETIC LANDSCAPE OF T CELLS, DESPITE EPIGENETIC CHANGES GOVERNING T CELL PHENOTYPE. CONCLUSION: HERE WE ARGUE THAT EPIGENETIC MODIFIERS CAN BE USED TO PRIME AND SENSITIZE T CELLS TO IMMUNOTHERAPY. ADMINISTERING EPITHERAPY IN CONJUNCTION WITH CHECKPOINT BLOCKADE COULD DECREASE T CELL EXHAUSTION AND IMMUNOTHERAPY RESISTANCE IN MANY CANCER TYPES. 2020 2 6851 40 [MOLECULAR PROFILES OF EXHAUSTED T CELLS AND THEIR IMPACT ON RESPONSE TO IMMUNE CHECKPOINT BLOCKADE]. T CELL EXHAUSTION IS INDUCED IN THE CONTEXT OF CHRONIC VIRUS INFECTION AND TUMOR MICROENVIRONMENT, IN WHICH CYTOTOXIC T CELLS ARE REPEATEDLY EXPOSED TO THE TARGET ANTIGEN AND DEPRIVED OF THEIR EFFECTOR FUNCTIONS. MULTIPLE STUDIES HAVE ALREADY SHOWN THE SIGNIFICANT IMPACT OF IMMUNE CHECKPOINT MOLECULES SUCH AS PD1 ON FUNCTIONAL PROPERTIES OF EXHAUSTED T CELLS. IN ADDITION TO THESE SIGNALS, EXHAUSTED T CELLS POSSESS DISTINCT TRANSCRIPTIONAL AND EPIGENETIC PROFILES COMPARED WITH CONVENTIONAL EFFECTOR AND MEMORY T CELLS. IMPORTANTLY, MOST OF THESE FEATURES ARE NOT AFFECTED BY IMMUNE CHECKPOINT BLOCKADE, SUGGESTING THAT GENETIC AND EPIGENETIC REMODELING OF T CELLS IS AN UNDERLYING MOLECULAR MECHANISM ESSENTIAL FOR T CELL EXHAUSTION. MOREOVER, IT HAS NOW BEEN EVIDENT THAT EXHAUSTED T CELLS ARE A HETEROGENEOUS CELL POPULATION COMPOSED OF DISTINCT T CELL SUBSETS, AND THESE FUNCTIONAL DIFFERENCES PROFOUNDLY AFFECT THERAPEUTIC EFFICACY OF CANCER IMMUNOTHERAPY. IN THIS REVIEW, I WILL DISCUSS RECENT STUDIES INVESTIGATING MOLECULAR MECHANISMS OF T CELL EXHAUSTION, INCLUDING NOVEL KEY MOLECULES ESSENTIALLY ASSOCIATED WITH T CELL EXHAUSTION. THESE FINDINGS ARE POTENTIALLY APPLICABLE TO REINVIGORATE EFFECTOR FUNCTIONS OF EXHAUSTED T CELLS. 2022 3 6060 38 THE DEVELOPMENT OF CD8 T-CELL EXHAUSTION HETEROGENEITY AND THE THERAPEUTIC POTENTIALS IN CANCER. CD8(+) T CELLS ARE ESSENTIAL LYMPHOCYTES WITH CYTOTOXIC PROPERTIES FOR ANTITUMOR IMMUNOTHERAPY. HOWEVER, DURING CHRONIC INFECTION OR TUMORIGENESIS, THESE CELLS OFTEN BECOME DYSFUNCTIONAL WITH A GRADUALLY DEPLETED ABILITY TO RELEASE CYTOKINES AND THE EXHIBITION OF REDUCED CYTOTOXICITY, THE STATE REFERRED TO AS "T-CELL EXHAUSTION" (TEX). THIS UNIQUE STATE WAS CHARACTERIZED BY THE INCREASING EXPRESSION OF INHIBITORY CHECKPOINT RECEPTORS, AND INTERVENTIONS TARGETING IMMUNE CHECKPOINT BLOCKADES (ICBS) HAVE BEEN CONSIDERED AS A PROMISING STRATEGY TO STIMULATE T-CELL KILLING. RECENT INVESTIGATIONS HAVE DEMONSTRATED THAT EXHAUSTED T CELLS NOT ONLY DISPLAY FUNCTIONAL, METABOLIC, TRANSCRIPTIONAL, AND EPIGENETIC DIFFERENCES BUT ALSO COMPRISE A HETEROGENEOUS GROUP OF CELLS. IN THIS REVIEW, WE SUMMARIZE THE CURRENT FINDINGS ON DYNAMIC DIFFERENTIATION PROCESS DURING TEX HETEROGENEITY DEVELOPMENT IN CANCER AND CHRONIC INFECTION. WE DISCUSS HOW THE RESPONSES TO IMMUNOTHERAPY ARE DETERMINED BY THESE DISTINCT SUBSETS AND HIGHLIGHT PROSPECTIVE APPROACHES FOR IMPROVING THE EFFICACY OF ICB THERAPY FOR CANCER BY LEVERAGING THE HETEROGENEITY OF T CELLS. 2023 4 2718 39 EXHAUSTED T CELLS AND EPIGENETIC STATUS. EXHAUSTED T CELLS ARE A GROUP OF DYSFUNCTIONAL T CELLS, WHICH ARE PRESENT IN CHRONIC INFECTIONS OR TUMORS. THE MOST SIGNIFICANT CHARACTERISTICS OF EXHAUSTED T CELLS ARE ATTENUATED EFFECTOR CYTOTOXICITY, REDUCED CYTOKINE PRODUCTION, AND UPREGULATION OF MULTIPLE INHIBITORY MOLECULAR RECEPTORS (E.G., PD-1, TIM-3, AND LAG-3). THE INTRACELLULAR METABOLIC CHANGES, ALTERED EXPRESSION OF TRANSCRIPTION FACTORS, AND A UNIQUE EPIGENETIC LANDSCAPE CONSTITUTE THE EXHAUSTION PROGRAM. RECENTLY, RESEARCHERS HAVE MADE PROGRESS IN UNDERSTANDING EXHAUSTED T CELLS, WITH THE DEFINITION AND IDENTIFICATION OF EXHAUSTED T CELLS CHANGING FROM PHENOTYPE-BASED TO BEING CLASSIFIED AT THE TRANSCRIPTIONAL AND EPIGENETIC LEVELS. RECENT STUDIES HAVE REVEALED THAT EXHAUSTED T CELLS CAN BE SEPARATED INTO TWO SUBGROUPS, NAMELY TCF1(+)PD-1(+) PROGENITOR-LIKE PRECURSOR EXHAUSTED CELLS AND TCF1(-)PD-1(+) TERMINALLY DIFFERENTIATED EXHAUSTED T CELLS. MOREOVER, THE PROGENITOR-LIKE PRECURSOR CELL POPULATION MAY BE A SUBSET OF T CELLS THAT CAN RESPOND TO IMMUNOTHERAPY. STUDIES HAVE ALSO FOUND THAT TOX INITIATES AND DOMINATES THE DEVELOPMENT OF EXHAUSTED T CELLS AT THE TRANSCRIPTIONAL AND EPIGENETIC LEVELS. TOX ALSO MAINTAINS T CELL SURVIVAL AND MAY AFFECT DECISIONS REGARDING TREATMENT STRATEGIES. IN THIS REVIEW, WE DISCUSS THE LATEST DEVELOPMENTS IN T CELL EXHAUSTION IN REGARDS TO DEFINITIONS, SUBPOPULATIONS, DEVELOPMENT MECHANISMS, DIFFERENCES IN DIVERSE DISEASES, AND TREATMENT PROSPECTS FOR EXHAUSTED T CELLS. FURTHERMORE, WE HYPOTHESIZE THAT THE EPIGENETIC STATE REGULATED BY TOX MIGHT BE THE KEY POINT, WHICH CAN DETERMINE THE REVERSIBILITY OF EXHAUSTION AND THE EFFICACY OF IMMUNOTHERAPY. 2020 5 2879 42 FUNDAMENTALS TO THERAPEUTICS: EPIGENETIC MODULATION OF CD8(+) T CELL EXHAUSTION IN THE TUMOR MICROENVIRONMENT. IN THE SETTING OF CHRONIC ANTIGEN EXPOSURE IN THE TUMOR MICROENVIRONMENT (TME), CYTOTOXIC CD8(+) T CELLS (CTLS) LOSE THEIR IMMUNE SURVEILLANCE CAPABILITIES AND ABILITY TO CLEAR TUMOR CELLS AS A RESULT OF THEIR DIFFERENTIATION INTO TERMINALLY EXHAUSTED CD8(+) T CELLS. IMMUNE CHECKPOINT BLOCKADE (ICB) THERAPIES REINVIGORATE EXHAUSTED CD8(+) T CELLS BY TARGETING SPECIFIC INHIBITORY RECEPTORS, THUS PROMOTING THEIR CYTOLYTIC ACTIVITY TOWARDS TUMOR CELLS. DESPITE EXCITING RESULTS WITH ICB THERAPIES, MANY PATIENTS WITH SOLID TUMORS STILL FAIL TO RESPOND TO SUCH THERAPIES AND PATIENTS WHO INITIALLY RESPOND CAN DEVELOP RESISTANCE. RECENTLY, THROUGH NEW SEQUENCING TECHNOLOGIES SUCH AS THE ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN WITH SEQUENCING (ATAC-SEQ), EPIGENETICS HAS BEEN APPRECIATED AS A CONTRIBUTING FACTOR THAT ENFORCES T CELL DIFFERENTIATION TOWARD EXHAUSTION IN THE TME. IMPORTANTLY, SPECIFIC EPIGENETIC ALTERATIONS AND EPIGENETIC FACTORS HAVE BEEN FOUND TO CONTROL CD8(+) T CELL EXHAUSTION PHENOTYPES. IN THIS REVIEW, WE WILL EXPLAIN THE BACKGROUND OF T CELL DIFFERENTIATION AND VARIOUS EXHAUSTION STATES AND DISCUSS HOW EPIGENETICS PLAY AN IMPORTANT ROLE IN THESE PROCESSES. THEN WE WILL OUTLINE SPECIFIC EPIGENETIC CHANGES AND CERTAIN EPIGENETIC AND TRANSCRIPTION FACTORS THAT ARE KNOWN TO CONTRIBUTE TO CD8(+) T CELL EXHAUSTION. WE WILL ALSO DISCUSS THE MOST RECENT METHODOLOGIES THAT ARE USED TO STUDY AND DISCOVER SUCH EPIGENETIC MODULATIONS. FINALLY, WE WILL EXPLAIN HOW EPIGENETIC REPROGRAMMING IS A PROMISING APPROACH THAT MIGHT FACILITATE THE DEVELOPMENT OF NOVEL EXHAUSTED T CELL-TARGETING IMMUNOTHERAPIES. 2022 6 1464 37 DISSECTING THE HETEROGENEITY OF EXHAUSTED T CELLS AT THE MOLECULAR LEVEL. OUR UNDERSTANDING OF MECHANISMS UNDERLYING T-CELL EXHAUSTION HAS BEEN REFINED BY ANALYSIS OF EXHAUSTED T CELLS AT THE MOLECULAR LEVEL. THE DEVELOPMENT AND FUNCTIONS OF EXHAUSTED T CELLS ARE REGULATED BY A NUMBER OF TRANSCRIPTION FACTORS, EPIGENETIC FACTORS AND METABOLIC ENZYMES. IN ADDITION, RECENT WORK TO DISSECT EXHAUSTED T CELLS AT THE SINGLE-CELL LEVEL HAS ENABLED US TO DISCOVER A PRECURSOR EXHAUSTED T-CELL SUBSET EQUIPPED WITH LONG-TERM SURVIVAL CAPACITY. STARTING FROM THE ANALYSIS OF MOUSE MODELS, THE EXISTENCE OF PRECURSOR EXHAUSTED T CELLS HAS ALSO BEEN DOCUMENTED IN HUMAN T CELLS IN THE CONTEXT OF CHRONIC VIRUS INFECTIONS OR TUMORS. CLINICAL DATA SUGGEST THAT EVALUATING THE QUALITY OF EXHAUSTED T CELLS ON THE BASIS OF THEIR DIFFERENTIATION STATUS MAY BE HELPFUL TO PREDICT THE THERAPEUTIC RESPONSE TO INHIBITION OF PROGRAMMED DEATH 1 (PD1). MOREOVER, BEYOND IMMUNE-CHECKPOINT BLOCKADE, NOVEL THERAPEUTIC APPROACHES TO RE-INVIGORATE EXHAUSTED T CELLS HAVE BEEN EXPLORED BASED ON MOLECULAR INSIGHTS INTO T-CELL EXHAUSTION. HERE I WILL DISCUSS KEY MOLECULAR PROFILES ASSOCIATED WITH THE DEVELOPMENT, MAINTENANCE AND DIFFERENTIATION OF EXHAUSTED T CELLS AND HOW THESE FINDINGS CAN BE APPLICABLE IN THE FIELD OF CANCER IMMUNOTHERAPY. 2022 7 5900 37 T-CELL EXHAUSTION IN ORGAN TRANSPLANTATION. EXHAUSTION OF T CELLS OCCURS IN RESPONSE TO LONG-TERM EXPOSURE TO SELF AND FOREIGN ANTIGENS. IT LIMITS T CELL CAPACITY TO PROLIFERATE AND PRODUCE CYTOKINES, LEADING TO AN IMPAIRED ABILITY TO CLEAR CHRONIC INFECTIONS OR ERADICATE TUMORS. T-CELL EXHAUSTION IS ASSOCIATED WITH A SPECIFIC TRANSCRIPTIONAL, EPIGENETIC, AND METABOLIC PROGRAM AND CHARACTERISTIC CELL SURFACE MARKERS' EXPRESSION. RECENT STUDIES HAVE BEGUN TO ELUCIDATE THE ROLE OF T-CELL EXHAUSTION IN TRANSPLANT. HIGHER LEVELS OF EXHAUSTED T CELLS HAVE BEEN ASSOCIATED WITH BETTER GRAFT FUNCTION IN KIDNEY TRANSPLANT RECIPIENTS. IN CONTRAST, REINVIGORATING EXHAUSTED T CELLS BY IMMUNE CHECKPOINT BLOCKADE THERAPIES, WHILE PROMOTING TUMOR CLEARANCE, INCREASES THE RISK OF ACUTE REJECTION. LYMPHOCYTE DEPLETION AND HIGH ALLOANTIGEN LOAD HAVE BEEN IDENTIFIED AS MAJOR DRIVERS OF T-CELL EXHAUSTION. THIS COULD ACCOUNT, AT LEAST IN PART, FOR THE REDUCED RATES OF ACUTE REJECTION IN ORGAN TRANSPLANT RECIPIENTS INDUCED WITH THYMOGLOBULIN AND FOR THE PRO-TOLEROGENIC EFFECTS OF A LARGE ORGAN SUCH AS THE LIVER. AMONG THE DRUGS THAT ARE WIDELY USED FOR MAINTENANCE IMMUNOSUPPRESSION, CALCINEURIN INHIBITORS HAVE A CONTRASTING INHIBITORY EFFECT ON EXHAUSTION OF T CELLS, WHILE THE INFLUENCE OF MTOR INHIBITORS IS STILL UNCLEAR. HARNESSING OR ENCOURAGING THE NATURAL PROCESSES OF EXHAUSTION MAY PROVIDE A NOVEL STRATEGY TO PROMOTE GRAFT SURVIVAL AND TRANSPLANTATION TOLERANCE. 2022 8 2367 33 EPIGENETIC REGULATION OF T CELL EXHAUSTION. CHRONIC ANTIGEN STIMULATION DURING VIRAL INFECTIONS AND CANCER CAN LEAD TO T CELL EXHAUSTION, WHICH IS CHARACTERIZED BY REDUCED EFFECTOR FUNCTION AND PROLIFERATION, AND THE EXPRESSION OF INHIBITORY IMMUNE CHECKPOINT RECEPTORS. RECENT STUDIES HAVE DEMONSTRATED THAT T CELL EXHAUSTION RESULTS IN WHOLESCALE EPIGENETIC REMODELING THAT CONFERS PHENOTYPIC STABILITY TO THESE CELLS AND PREVENTS T CELL REINVIGORATION BY CHECKPOINT BLOCKADE. HERE, WE REVIEW FOUNDATIONAL TECHNOLOGIES TO PROFILE THE EPIGENOME AT MULTIPLE SCALES, INCLUDING MAPPING THE LOCATIONS OF TRANSCRIPTION FACTORS AND HISTONE MODIFICATIONS, DNA METHYLATION AND THREE-DIMENSIONAL GENOME CONFORMATION. WE DISCUSS HOW THESE TECHNOLOGIES HAVE ELUCIDATED THE DEVELOPMENT AND EPIGENETIC REGULATION OF EXHAUSTED T CELLS AND FUNCTIONAL IMPLICATIONS ACROSS VIRAL INFECTION, CANCER, AUTOIMMUNITY AND ENGINEERED T CELL THERAPIES. FINALLY, WE COVER EMERGING MULTI-OMIC AND GENOME ENGINEERING TECHNOLOGIES, CURRENT AND UPCOMING OPPORTUNITIES TO APPLY THESE TO T CELL EXHAUSTION, AND THERAPEUTIC OPPORTUNITIES FOR T CELL ENGINEERING IN THE CLINIC. 2022 9 451 37 APPLICATION OF ATAC-SEQ IN TUMOR-SPECIFIC T CELL EXHAUSTION. RESEARCHES SHOW THAT CHRONIC VIRAL INFECTION AND PERSISTENT ANTIGEN AND/OR INFLAMMATORY SIGNAL EXPOSURE IN CANCER CAUSES THE FUNCTIONAL STATUS OF T CELLS TO BE ALTERED, MAINLY BY MAJOR CHANGES IN THE EPIGENETIC AND METABOLIC ENVIRONMENT, WHICH THEN LEADS TO T CELL EXHAUSTION. THE DISCOVERY OF THE IMMUNE CHECKPOINT PATHWAY IS AN IMPORTANT MILESTONE IN UNDERSTANDING AND REVERSING T CELL EXHAUSTION. ANTIBODIES TARGETING THESE PATHWAYS HAVE SHOWN SUPERIOR ABILITY TO REVERSE T CELL EXHAUSTION. HOWEVER, THERE ARE STILL SOME LIMITATIONS IN IMMUNE CHECKPOINT BLOCKING THERAPY, SUCH AS THE SHORT-TERM NATURE OF THERAPEUTIC EFFECTS AND HIGH INDIVIDUAL HETEROGENEITY. ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN WITH SEQUENCING(ATAC-SEQ) IS A METHOD USED TO ANALYZE THE ACCESSIBILITY OF WHOLE-GENOME CHROMATIN. IT USES HYPERACTIVE TN5 TRANSPOSASE TO ASSESS CHROMATIN ACCESSIBILITY. RECENTLY, A GROWING NUMBER OF STUDIES HAVE REPORTED THAT ATAC-SEQ CAN BE USED TO CHARACTERIZE THE DYNAMIC CHANGES OF EPIGENETICS IN THE PROCESS OF T CELL EXHAUSTION. IT HAS BEEN DETERMINED THAT IMMUNE CHECKPOINT BLOCKING CAN ONLY TEMPORARILY RESTORE THE FUNCTION OF EXHAUSTED T CELLS BECAUSE OF AN IRREVERSIBLE CHANGE IN THE EPIGENETICS OF EXHAUSTED T CELLS. IN THIS STUDY, WE REVIEW THE LATEST DEVELOPMENTS, WHICH PROVIDE A CLEARER MOLECULAR UNDERSTANDING OF T CELL EXHAUSTION, REVEAL POTENTIAL NEW THERAPEUTIC TARGETS FOR PERSISTENT VIRAL INFECTION AND CANCER, AND PROVIDE NEW INSIGHTS FOR DESIGNING EFFECTIVE IMMUNOTHERAPY FOR TREATING CANCER AND CHRONIC INFECTION. 2023 10 1054 35 CLINICAL IMPLICATIONS OF T CELL EXHAUSTION FOR CANCER IMMUNOTHERAPY. IMMUNOTHERAPY HAS BEEN A REMARKABLE CLINICAL ADVANCEMENT IN THE TREATMENT OF CANCER. T CELLS ARE PIVOTAL TO THE EFFICACY OF CURRENT CANCER IMMUNOTHERAPIES, INCLUDING IMMUNE-CHECKPOINT INHIBITORS AND ADOPTIVE CELL THERAPIES. HOWEVER, CANCER IS ASSOCIATED WITH T CELL EXHAUSTION, A HYPOFUNCTIONAL STATE CHARACTERIZED BY PROGRESSIVE LOSS OF T CELL EFFECTOR FUNCTIONS AND SELF-RENEWAL CAPACITY. THE 'UN-EXHAUSTING' OF T CELLS IN THE TUMOUR MICROENVIRONMENT IS COMMONLY REGARDED AS A KEY MECHANISM OF ACTION FOR IMMUNE-CHECKPOINT INHIBITORS, AND T CELL EXHAUSTION IS CONSIDERED A PATHWAY OF RESISTANCE FOR CELLULAR IMMUNOTHERAPIES. SEVERAL ELEGANT STUDIES HAVE PROVIDED IMPORTANT INSIGHTS INTO THE TRANSCRIPTIONAL AND EPIGENETIC PROGRAMMES THAT GOVERN T CELL EXHAUSTION. IN THIS REVIEW, WE HIGHLIGHT RECENT DISCOVERIES RELATED TO THE IMMUNOBIOLOGY OF T CELL EXHAUSTION THAT OFFER A MORE NUANCED PERSPECTIVE BEYOND THIS HYPOFUNCTIONAL STATE BEING ENTIRELY UNDESIRABLE. WE REVIEW EVIDENCE THAT T CELL EXHAUSTION MIGHT BE AS MUCH A REFLECTION AS IT IS THE CAUSE OF POOR TUMOUR CONTROL. FURTHERMORE, WE HYPOTHESIZE THAT, IN CERTAIN CONTEXTS OF CHRONIC ANTIGEN STIMULATION, INTERRUPTION OF THE EXHAUSTION PROGRAMME MIGHT IMPAIR T CELL PERSISTENCE. THEREFORE, THE PRIORITIZATION OF INTERVENTIONS THAT MITIGATE THE DEVELOPMENT OF T CELL EXHAUSTION, INCLUDING ORTHOGONAL CYTOREDUCTION THERAPIES AND NOVEL CELLULAR ENGINEERING STRATEGIES, MIGHT ULTIMATELY CONFER SUPERIOR CLINICAL OUTCOMES AND THE GREATEST ADVANCES IN CANCER IMMUNOTHERAPY. 2022 11 790 28 CELLULAR AND MOLECULAR MECHANISMS OF CD8(+) T CELL DIFFERENTIATION, DYSFUNCTION AND EXHAUSTION. T CELLS FOLLOW A TRIPHASIC DISTINCT PATHWAY OF ACTIVATION, PROLIFERATION AND DIFFERENTIATION BEFORE BECOMING FUNCTIONALLY AND PHENOTYPICALLY "EXHAUSTED" IN SETTINGS OF CHRONIC INFECTION, AUTOIMMUNITY AND IN CANCER. EXHAUSTED T CELLS PROGRESSIVELY LOSE CANONICAL EFFECTOR FUNCTIONS, EXHIBIT ALTERED TRANSCRIPTIONAL NETWORKS AND EPIGENETIC SIGNATURES AND GAIN CONSTITUTIVE EXPRESSION OF A BROAD COINHIBITORY RECEPTOR SUITE. THIS REVIEW OUTLINES RECENT ADVANCES IN OUR UNDERSTANDING OF EXHAUSTED T CELL BIOLOGY AND EXAMINES CELLULAR AND MOLECULAR MECHANISMS BY WHICH A STATE OF DYSFUNCTION OR EXHAUSTION IS ESTABLISHED, AND MECHANISMS BY WHICH EXHAUSTED T CELLS MAY STILL CONTRIBUTE TO PATHOGEN OR TUMOUR CONTROL. FURTHER, THIS REVIEW DESCRIBES OUR UNDERSTANDING OF EXHAUSTED T CELL HETEROGENEITY AND OUTLINES THE MECHANISMS BY WHICH CHECKPOINT BLOCKADE DIFFERENTIALLY ENGAGES EXHAUSTED T CELL SUBSETS TO OVERCOME EXHAUSTION AND RECOVER T CELL FUNCTION. 2020 12 5248 36 PROGRAMMED CELL DEATH 1-DIRECTED IMMUNOTHERAPY FOR ENHANCING T-CELL FUNCTION. T-CELL EXHAUSTION IS A UNIQUE STATE THAT APPEARS DURING MANY CHRONIC INFECTIONS AND CANCER AND IS CHARACTERIZED BY LOSS OF PROLIFERATIVE CAPACITY AND EFFECTOR FUNCTION. COMPLEX MECHANISMS ARE INVOLVED IN THIS T-CELL DYSFUNCTION BUT AN INHIBITORY RECEPTOR, PD-1, HAS BEEN IDENTIFIED AS A MAJOR REGULATOR OF T-CELL EXHAUSTION. BLOCKADE OF THE PD-1 PATHWAY CAN REINVIGORATE EXHAUSTED T CELLS, RESULTING IN BETTER CONTROL OF CHRONIC INFECTIONS AND CANCER. NOTABLY, RECENT CLINICAL STUDIES HAVE REVEALED THAT PD-1-DIRECTED IMMUNOTHERAPY IS HIGHLY EFFECTIVE IN CANCER PATIENTS, DEMONSTRATING THAT PD-1 IS A PROMISING THERAPEUTIC TARGET IN HUMANS. IN THIS REVIEW, WE SUMMARIZE OUR CURRENT UNDERSTANDING OF THE EPIGENETIC REGULATION OF PD-1 EXPRESSION IN T CELLS AND DISCUSS POTENTIAL COMBINATION THERAPY WITH PD-1 BLOCKADE TOWARD DEVELOPING MORE EFFECTIVE TREATMENT FOR CHRONIC INFECTIONS AND CANCER. 2013 13 3895 31 LANDSCAPES AND MECHANISMS OF CD8(+) T CELL EXHAUSTION IN GASTROINTESTINAL CANCER. CD8(+) T CELLS, A CYTOTOXIC T LYMPHOCYTE, ARE A KEY COMPONENT OF THE TUMOR IMMUNE SYSTEM, BUT THEY ENTER A HYPOREACTIVE T CELL STATE IN LONG-TERM CHRONIC INFLAMMATION, AND HOW TO RESCUE THIS DEPLETED STATE IS A KEY DIRECTION OF RESEARCH. CURRENT STUDIES ON CD8(+) T CELL EXHAUSTION HAVE FOUND THAT THE MECHANISMS RESPONSIBLE FOR THEIR HETEROGENEITY AND DIFFERENTIAL KINETICS MAY BE CLOSELY RELATED TO TRANSCRIPTION FACTORS AND EPIGENETIC REGULATION, WHICH MAY SERVE AS BIOMARKERS AND POTENTIAL IMMUNOTHERAPEUTIC TARGETS TO GUIDE TREATMENT. ALTHOUGH THE IMPORTANCE OF T CELL EXHAUSTION IN TUMOR IMMUNOTHERAPY CANNOT BE OVERSTATED, STUDIES HAVE POINTED OUT THAT GASTRIC CANCER TISSUES HAVE A BETTER ANTI-TUMOR T CELL COMPOSITION COMPARED TO OTHER CANCER TISSUES, WHICH MAY INDICATE THAT GASTROINTESTINAL CANCERS HAVE MORE PROMISING PROSPECTS FOR THE DEVELOPMENT OF PRECISION-TARGETED IMMUNOTHERAPY. THEREFORE, THE PRESENT STUDY WILL FOCUS ON THE MECHANISMS INVOLVED IN THE DEVELOPMENT OF CD8(+) T CELL EXHAUSTION, AND THEN REVIEW THE LANDSCAPES AND MECHANISMS OF T CELL EXHAUSTION IN GASTROINTESTINAL CANCER AS WELL AS CLINICAL APPLICATIONS, WHICH WILL PROVIDE A CLEAR VISION FOR THE DEVELOPMENT OF FUTURE IMMUNOTHERAPIES. 2023 14 771 35 CD8(+) T CELL EXHAUSTION. CD8(+) T CELLS ARE IMPORTANT FOR THE PROTECTIVE IMMUNITY AGAINST INTRACELLULAR PATHOGENS AND TUMOR. IN THE CASE OF CHRONIC INFECTION OR CANCER, CD8(+) T CELLS ARE EXPOSED TO PERSISTENT ANTIGEN AND/OR INFLAMMATORY SIGNALS. THIS EXCESSIVE AMOUNT OF SIGNALS OFTEN LEADS CD8(+) T CELLS TO GRADUAL DETERIORATION OF T CELL FUNCTION, A STATE CALLED "EXHAUSTION." EXHAUSTED T CELLS ARE CHARACTERIZED BY PROGRESSIVE LOSS OF EFFECTOR FUNCTIONS (CYTOKINE PRODUCTION AND KILLING FUNCTION), EXPRESSION OF MULTIPLE INHIBITORY RECEPTORS (SUCH AS PD-1 AND LAG3), DYSREGULATED METABOLISM, POOR MEMORY RECALL RESPONSE, AND HOMEOSTATIC PROLIFERATION. THESE ALTERED FUNCTIONS ARE CLOSELY RELATED WITH ALTERED TRANSCRIPTIONAL PROGRAM AND EPIGENETIC LANDSCAPE THAT CLEARLY DISTINGUISH EXHAUSTED T CELLS FROM NORMAL EFFECTOR AND MEMORY T CELLS. T CELL EXHAUSTION IS OFTEN ASSOCIATED WITH INEFFICIENT CONTROL OF PERSISTING INFECTIONS AND CANCERS, BUT RE-INVIGORATION OF EXHAUSTED T CELLS WITH INHIBITORY RECEPTOR BLOCKADE CAN PROMOTE IMPROVED IMMUNITY AND DISEASE OUTCOME. ACCUMULATING EVIDENCES SUPPORT THE THERAPEUTIC POTENTIAL OF TARGETING EXHAUSTED T CELLS. HOWEVER, EXHAUSTED T CELLS COMPRISE HETEROGENOUS CELL POPULATION WITH DISTINCT RESPONSIVENESS TO INTERVENTION. UNDERSTANDING MOLECULAR MECHANISM OF T CELL EXHAUSTION IS ESSENTIAL TO ESTABLISH RATIONAL IMMUNOTHERAPEUTIC INTERVENTIONS. 2019 15 2056 29 EPIGENETIC CONTROL OF CD8(+) T CELL DIFFERENTIATION. UPON STIMULATION, SMALL NUMBERS OF NAIVE CD8(+) T CELLS PROLIFERATE AND DIFFERENTIATE INTO A VARIETY OF MEMORY AND EFFECTOR CELL TYPES. CD8(+) T CELLS CAN PERSIST FOR YEARS AND KILL TUMOUR CELLS AND VIRALLY INFECTED CELLS. THE FUNCTIONAL AND PHENOTYPIC CHANGES THAT OCCUR DURING CD8(+) T CELL DIFFERENTIATION ARE WELL CHARACTERIZED, BUT THE EPIGENETIC STATES THAT UNDERLIE THESE CHANGES ARE INCOMPLETELY UNDERSTOOD. HERE, WE REVIEW THE EPIGENETIC PROCESSES THAT DIRECT CD8(+) T CELL DIFFERENTIATION AND FUNCTION. WE FOCUS ON EPIGENETIC MODIFICATION OF DNA AND ASSOCIATED HISTONES AT GENES AND THEIR REGULATORY ELEMENTS. WE ALSO DESCRIBE STRUCTURAL CHANGES IN CHROMATIN ORGANIZATION THAT AFFECT GENE EXPRESSION. FINALLY, WE EXAMINE THE TRANSLATIONAL POTENTIAL OF EPIGENETIC INTERVENTIONS TO IMPROVE CD8(+) T CELL FUNCTION IN INDIVIDUALS WITH CHRONIC INFECTIONS AND CANCER. 2018 16 5414 26 REGULATION OF CD8(+) T MEMORY AND EXHAUSTION BY THE MTOR SIGNALS. CD8(+) T CELLS ARE THE KEY EXECUTIONERS OF THE ADAPTIVE IMMUNE ARM, WHICH MEDIATES ANTITUMOR AND ANTIVIRAL IMMUNITY. NAIVE CD8(+) T CELLS DEVELOP IN THE THYMUS AND ARE QUICKLY ACTIVATED IN THE PERIPHERY AFTER ENCOUNTERING A COGNATE ANTIGEN, WHICH INDUCES THESE CELLS TO PROLIFERATE AND DIFFERENTIATE INTO EFFECTOR CELLS THAT FIGHT THE INITIAL INFECTION. SIMULTANEOUSLY, A FRACTION OF THESE CELLS BECOME LONG-LIVED MEMORY CD8(+) T CELLS THAT COMBAT FUTURE INFECTIONS. NOTABLY, THE GENERATION AND MAINTENANCE OF MEMORY CELLS IS PROFOUNDLY AFFECTED BY VARIOUS IN VIVO CONDITIONS, SUCH AS THE MODE OF PRIMARY ACTIVATION (E.G., ACUTE VS. CHRONIC IMMUNIZATION) OR FLUCTUATIONS IN HOST METABOLIC, INFLAMMATORY, OR AGING FACTORS. THEREFORE, MANY T CELLS MAY BE LOST OR BECOME EXHAUSTED AND NO LONGER FUNCTIONAL. COMPLICATED INTRACELLULAR SIGNALING PATHWAYS, TRANSCRIPTION FACTORS, EPIGENETIC MODIFICATIONS, AND METABOLIC PROCESSES ARE INVOLVED IN THIS PROCESS. THEREFORE, UNDERSTANDING THE CELLULAR AND MOLECULAR BASIS FOR THE GENERATION AND FATE OF MEMORY AND EXHAUSTED CD8(+) CELLS IS CENTRAL FOR HARNESSING CELLULAR IMMUNITY. IN THIS REVIEW, WE FOCUS ON MAMMALIAN TARGET OF RAPAMYCIN (MTOR), PARTICULARLY SIGNALING MEDIATED BY MTOR COMPLEX (MTORC) 2 IN MEMORY AND EXHAUSTED CD8(+) T CELLS AT THE MOLECULAR LEVEL. 2023 17 4340 32 MIGRATION OF STEM-LIKE CD8 T CELLS BETWEEN TISSUE MICROENVIRONMENTS UNDERPINS SUCCESSFUL ANTI-TUMOUR IMMUNE RESPONSES. THE CLINICAL SUCCESS OF IMMUNE CHECKPOINT BLOCKADE IN SOME PATIENTS HAS TRANSFORMED TREATMENT APPROACHES IN CANCER AND OFFERS THE HOPE OF DURABLE CURATIVE RESPONSES. BUILDING FROM STUDIES OF CHRONIC INFECTION, THE COMPOSITION OF TUMOUR INFILTRATING LYMPHOCYTES AND IN PARTICULAR, THE SPECTRUM OF EXHAUSTED CD8 T CELLS HAS NOW BEEN CHARACTERIZED IN DETAIL, PROFILING THE PHENOTYPE, FUNCTION, TRANSCRIPTIONAL REGULATION AND EVEN THE EPIGENETIC CHANGES. HOWEVER, WHAT REMAINS LESS CLEAR IS HOW INTRATUMOURAL IMMUNE CELLS INTERFACE WITH POPULATIONS IN THE PERIPHERY, BOTH IN TERMS OF SUSTAINING THE RESPONSE IN CANCER, BUT ALSO IN ESTABLISHING SYSTEMIC MEMORY RESPONSES THAT CAN PROVIDE LONG-TERM PROTECTION. HERE WE WILL SUCCINCTLY REVIEW THE CURRENT UNDERSTANDING OF THE ANTI-TUMOUR RESPONSE, CONSIDER THE TISSUE MICROENVIRONMENTS THAT SUPPORT KEY CELLULAR SUBSETS AND THE EXTENT TO WHICH CELLULAR MIGRATION BETWEEN THESE SITES IMPACTS THE RESPONSE. 2023 18 6014 23 THE ARCHITECTURAL DESIGN OF CD8+ T CELL RESPONSES IN ACUTE AND CHRONIC INFECTION: PARALLEL STRUCTURES WITH DIVERGENT FATES. IN RESPONSE TO INFECTION, T CELLS ADOPT A RANGE OF DIFFERENTIATION STATES, CREATING NUMEROUS HETEROGENEOUS SUBSETS THAT EXHIBIT DIFFERENT PHENOTYPES, FUNCTIONS, AND MIGRATION PATTERNS. THIS T CELL HETEROGENEITY IS A UNIVERSAL FEATURE OF T CELL IMMUNITY, NEEDED TO EFFECTIVELY CONTROL PATHOGENS IN A CONTEXT-DEPENDENT MANNER AND GENERATE LONG-LIVED IMMUNITY TO THOSE PATHOGENS. HERE, WE REVIEW NEW INSIGHTS INTO DIFFERENTIATION STATE DYNAMICS AND POPULATION HETEROGENEITY OF CD8+ T CELLS IN ACUTE AND CHRONIC VIRAL INFECTIONS AND CANCER AND HIGHLIGHT THE PARALLELS AND DISTINCTIONS BETWEEN ACUTE AND CHRONIC ANTIGEN STIMULATION SETTINGS. WE FOCUS ON TRANSCRIPTIONAL AND EPIGENETIC NETWORKS THAT MODULATE THE PLASTICITY AND TERMINAL DIFFERENTIATION OF ANTIGEN-SPECIFIC CD8+ T CELLS AND GENERATE FUNCTIONALLY DIVERSE T CELL SUBSETS WITH DIFFERENT ROLES TO COMBAT INFECTION AND CANCER. 2021 19 3288 34 HIERARCHICAL TRANSCRIPTIONAL NETWORK GOVERNING HETEROGENEOUS T CELL EXHAUSTION AND ITS IMPLICATIONS FOR IMMUNE CHECKPOINT BLOCKADE. THE FUNDAMENTAL PRINCIPLE OF IMMUNE CHECKPOINT BLOCKADE (ICB) IS TO PROTECT TUMOR-INFILTRATING T CELLS FROM BEING EXHAUSTED. DESPITE THE REMARKABLE SUCCESS ACHIEVED BY ICB TREATMENT, ONLY A SMALL GROUP OF PATIENTS BENEFIT FROM IT. CHARACTERIZED BY A HYPOFUNCTIONAL STATE WITH THE EXPRESSION OF MULTIPLE INHIBITORY RECEPTORS, EXHAUSTED T (TEX) CELLS ARE A MAJOR OBSTACLE IN IMPROVING ICB. T CELL EXHAUSTION IS A PROGRESSIVE PROCESS WHICH ADAPTS TO PERSISTENT ANTIGEN STIMULATION IN CHRONIC INFECTIONS AND CANCERS. IN THIS REVIEW, WE ELUCIDATE THE HETEROGENEITY OF TEX CELLS AND OFFER NEW INSIGHTS INTO THE HIERARCHICAL TRANSCRIPTIONAL REGULATION OF T CELL EXHAUSTION. FACTORS AND SIGNALING PATHWAYS THAT INDUCE AND PROMOTE EXHAUSTION ARE ALSO SUMMARIZED. MOREOVER, WE REVIEW THE EPIGENETIC AND METABOLIC ALTERATIONS OF TEX CELLS AND DISCUSS HOW PD-1 SIGNALING AFFECTS THE BALANCE BETWEEN T CELL ACTIVATION AND EXHAUSTION, AIMING TO PROVIDE MORE THERAPEUTIC TARGETS FOR APPLICATIONS OF COMBINATIONAL IMMUNOTHERAPIES. 2023 20 4726 23 NOT-SO-OPPOSITE ENDS OF THE SPECTRUM: CD8(+) T CELL DYSFUNCTION ACROSS CHRONIC INFECTION, CANCER AND AUTOIMMUNITY. CD8(+) T CELLS ARE CRITICAL MEDIATORS OF CYTOTOXIC EFFECTOR FUNCTION IN INFECTION, CANCER AND AUTOIMMUNITY. IN CANCER AND CHRONIC VIRAL INFECTION, CD8(+) T CELLS UNDERGO A PROGRESSIVE LOSS OF CYTOKINE PRODUCTION AND CYTOTOXICITY, A STATE TERMED T CELL EXHAUSTION. IN AUTOIMMUNITY, AUTOREACTIVE CD8(+) T CELLS RETAIN THE CAPACITY TO EFFECTIVELY MEDIATE THE DESTRUCTION OF HOST TISSUES. ALTHOUGH THE CLINICAL OUTCOME DIFFERS IN EACH CONTEXT, CD8(+) T CELLS ARE CHRONICALLY EXPOSED TO ANTIGEN IN ALL THREE. THESE CHRONICALLY STIMULATED CD8(+) T CELLS SHARE SOME COMMON PHENOTYPIC FEATURES, AS WELL AS TRANSCRIPTIONAL AND EPIGENETIC PROGRAMMING, ACROSS DISEASE CONTEXTS. A BETTER UNDERSTANDING OF THESE CD8(+) T CELL STATES MAY REVEAL NOVEL STRATEGIES TO AUGMENT CLEARANCE OF CHRONIC VIRAL INFECTION AND CANCER AND TO MITIGATE SELF-REACTIVITY LEADING TO TISSUE DAMAGE IN AUTOIMMUNITY. 2021