1 4178 71 MEMORY T-CELL HETEROGENEITY AND TERMINOLOGY. IMMUNOLOGICAL MEMORY AND EXHAUSTION ARE FUNDAMENTAL FEATURES OF ADAPTIVE IMMUNITY. RECENT ADVANCES REVEAL INCREASING HETEROGENEITY AND DIVERSITY AMONG CD8 T-CELL SUBSETS, RESULTING IN NEW SUBSETS TO ANNOTATE AND UNDERSTAND. HERE, WE REVIEW OUR CURRENT KNOWLEDGE OF DIFFERENTIATION AND MAINTENANCE OF MEMORY AND EXHAUSTED CD8 T CELLS, INCLUDING PHENOTYPIC CLASSIFICATION, DEVELOPMENTAL PATHS, TRANSCRIPTIONAL AND EPIGENETIC FEATURES, AND CELL INTRINSIC AND EXTRINSIC FACTORS. ADDITIONALLY, WE USE THIS OUTLINE TO DISCUSS THE NOMENCLATURE OF EFFECTOR, MEMORY, AND EXHAUSTED CD8 T CELLS. FINALLY, WE DISCUSS HOW NEW FINDINGS ABOUT THESE CELL TYPES MAY IMPACT THE THERAPEUTIC EFFICACY AND DEVELOPMENT OF IMMUNOTHERAPIES TARGETING EFFECTOR, MEMORY, AND/OR EXHAUSTED CD8 T CELLS IN CHRONIC INFECTIONS AND CANCER. 2021 2 6851 32 [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 34 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 5896 35 T CELLS IN HEALTH AND DISEASE. T CELLS ARE CRUCIAL FOR IMMUNE FUNCTIONS TO MAINTAIN HEALTH AND PREVENT DISEASE. T CELL DEVELOPMENT OCCURS IN A STEPWISE PROCESS IN THE THYMUS AND MAINLY GENERATES CD4(+) AND CD8(+) T CELL SUBSETS. UPON ANTIGEN STIMULATION, NAIVE T CELLS DIFFERENTIATE INTO CD4(+) HELPER AND CD8(+) CYTOTOXIC EFFECTOR AND MEMORY CELLS, MEDIATING DIRECT KILLING, DIVERSE IMMUNE REGULATORY FUNCTION, AND LONG-TERM PROTECTION. IN RESPONSE TO ACUTE AND CHRONIC INFECTIONS AND TUMORS, T CELLS ADOPT DISTINCT DIFFERENTIATION TRAJECTORIES AND DEVELOP INTO A RANGE OF HETEROGENEOUS POPULATIONS WITH VARIOUS PHENOTYPE, DIFFERENTIATION POTENTIAL, AND FUNCTIONALITY UNDER PRECISE AND ELABORATE REGULATIONS OF TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS. ABNORMAL T-CELL IMMUNITY CAN INITIATE AND PROMOTE THE PATHOGENESIS OF AUTOIMMUNE DISEASES. IN THIS REVIEW, WE SUMMARIZE THE CURRENT UNDERSTANDING OF T CELL DEVELOPMENT, CD4(+) AND CD8(+) T CELL CLASSIFICATION, AND DIFFERENTIATION IN PHYSIOLOGICAL SETTINGS. WE FURTHER ELABORATE THE HETEROGENEITY, DIFFERENTIATION, FUNCTIONALITY, AND REGULATION NETWORK OF CD4(+) AND CD8(+) T CELLS IN INFECTIOUS DISEASE, CHRONIC INFECTION AND TUMOR, AND AUTOIMMUNE DISEASE, HIGHLIGHTING THE EXHAUSTED CD8(+) T CELL DIFFERENTIATION TRAJECTORY, CD4(+) T CELL HELPER FUNCTION, T CELL CONTRIBUTIONS TO IMMUNOTHERAPY AND AUTOIMMUNE PATHOGENESIS. WE ALSO DISCUSS THE DEVELOPMENT AND FUNCTION OF GAMMADELTA T CELLS IN TISSUE SURVEILLANCE, INFECTION, AND TUMOR IMMUNITY. FINALLY, WE SUMMARIZED CURRENT T-CELL-BASED IMMUNOTHERAPIES IN BOTH CANCER AND AUTOIMMUNE DISEASES, WITH AN EMPHASIS ON THEIR CLINICAL APPLICATIONS. A BETTER UNDERSTANDING OF T CELL IMMUNITY PROVIDES INSIGHT INTO DEVELOPING NOVEL PROPHYLACTIC AND THERAPEUTIC STRATEGIES IN HUMAN DISEASES. 2023 5 790 27 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 6 769 40 CD8 T CELL EXHAUSTION DURING CHRONIC VIRAL INFECTION AND CANCER. EXHAUSTED CD8 T (TEX) CELLS ARE A DISTINCT CELL LINEAGE THAT ARISE DURING CHRONIC INFECTIONS AND CANCERS IN ANIMAL MODELS AND HUMANS. TEX CELLS ARE CHARACTERIZED BY PROGRESSIVE LOSS OF EFFECTOR FUNCTIONS, HIGH AND SUSTAINED INHIBITORY RECEPTOR EXPRESSION, METABOLIC DYSREGULATION, POOR MEMORY RECALL AND HOMEOSTATIC SELF-RENEWAL, AND DISTINCT TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS. THE ABILITY TO REINVIGORATE TEX CELLS THROUGH INHIBITORY RECEPTOR BLOCKADE, SUCH AS ALPHAPD-1, HIGHLIGHTS THE THERAPEUTIC POTENTIAL OF TARGETING THIS POPULATION. EMERGING INSIGHTS INTO THE MECHANISMS OF EXHAUSTION ARE INFORMING IMMUNOTHERAPIES FOR CANCER AND CHRONIC INFECTIONS. HOWEVER, LIKE OTHER IMMUNE CELLS, TEX CELLS ARE HETEROGENEOUS AND INCLUDE PROGENITOR AND TERMINAL SUBSETS WITH UNIQUE CHARACTERISTICS AND RESPONSES TO CHECKPOINT BLOCKADE. HERE, WE REVIEW OUR CURRENT UNDERSTANDING OF TEX CELL BIOLOGY, INCLUDING THE DEVELOPMENTAL PATHS, TRANSCRIPTIONAL AND EPIGENETIC FEATURES, AND CELL INTRINSIC AND EXTRINSIC FACTORS CONTRIBUTING TO EXHAUSTION AND HOW THIS KNOWLEDGE MAY INFORM THERAPEUTIC TARGETING OF TEX CELLS IN CHRONIC INFECTIONS, AUTOIMMUNITY, AND CANCER. 2019 7 6014 24 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 8 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 9 2367 29 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 10 2718 29 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 11 2879 32 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 12 1464 32 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 13 771 27 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 14 5407 24 REGULATION AND IMMUNOTHERAPEUTIC TARGETING OF THE EPIGENOME IN EXHAUSTED CD8 T CELL RESPONSES. EXHAUSTION IS A STATE OF CD8 T CELL DIFFERENTIATION THAT OCCURS IN SETTINGS OF CHRONIC AG SUCH AS TUMORS, CHRONIC VIRAL INFECTION, AND AUTOIMMUNITY. CELLULAR DIFFERENTIATION IS DRIVEN BY A SERIES OF ENVIRONMENTAL SIGNALS THAT PROMOTE EPIGENETIC LANDSCAPES THAT SET TRANSCRIPTOMES NEEDED FOR FUNCTION. FOR CD8 T CELLS, THE EPIGENOME THAT UNDERLIES EXHAUSTION IS DISTINCT FROM EFFECTOR AND MEMORY CELL DIFFERENTIATION, SUGGESTING THAT SIGNALS EARLY ON SET IN MOTION A PROCESS WHERE THE EPIGENOME IS MODIFIED TO PROMOTE A TRAJECTORY TOWARD A DYSFUNCTIONAL STATE. ALTHOUGH WE KNOW MANY SIGNALS THAT PROMOTE EXHAUSTION, PUTTING THIS IN THE CONTEXT OF THE EPIGENETIC CHANGES THAT OCCUR DURING DIFFERENTIATION HAS BEEN LESS CLEAR. IN THIS REVIEW, WE AIM TO SUMMARIZE THE EPIGENETIC CHANGES ASSOCIATED WITH EXHAUSTION IN THE CONTEXT OF SIGNALS THAT PROMOTE IT, HIGHLIGHTING IMMUNOTHERAPEUTIC STUDIES THAT SUPPORT THESE OBSERVATIONS OR AREAS FOR FUTURE THERAPEUTIC OPPORTUNITIES. 2023 15 6319 35 THE ROAD LESS TAKEN: LESS APPRECIATED PATHWAYS FOR MANIPULATING CD8(+) T CELL EXHAUSTION. EXHAUSTED CD8(+) T (TEX) CELLS ARE A DISTINCT CELL POPULATION THAT ARISE DURING PERSISTENT ANTIGEN EXPOSURE IN THE CONTEXT OF CHRONIC INFECTIONS AND CANCERS. ALTHOUGH CHARACTERIZED BY PROGRESSIVE LOSS OF EFFECTOR FUNCTIONS, HIGH AND SUSTAINED INHIBITORY RECEPTOR EXPRESSION AND DISTINCT TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS, TEX CELLS ARE HETEROGENEOUS. AMONG THESE, A SELF-RENEWING TCF-1(+) TEX POPULATION, HAVING UNIQUE CHARACTERISTICS AND THE ABILITY TO RESPOND TO IMMUNE-CHECKPOINT BLOCKADE, GIVES RISE TO TCF-1(-) TERMINALLY TEX CELLS. THESE TCF-1(+) CELLS HAVE STEM CELL-LIKE PROPERTIES SIMILAR TO MEMORY T CELL POPULATIONS, BUT THE SIGNALS THAT REGULATE THE DEVELOPMENTAL PATHWAYS AND RELATIONSHIPS AMONG EXHAUSTED CELL POPULATIONS ARE STILL UNCLEAR. HERE, WE REVIEW OUR CURRENT UNDERSTANDING OF TEX CELL BIOLOGY, AND DISCUSS SOME LESS APPRECIATED MOLECULES AND PATHWAYS AFFECTING T CELL EXHAUSTION. WE HIGHLIGHT TWO CO-STIMULATORY RECEPTORS, CD226 AND CD137, AND THEIR ROLE IN INDUCING OR RESTRAINING T CELL EXHAUSTION, AS WELL AS SIGNALING PATHWAYS THAT MAY BE AMENABLE TO PHARMACOLOGICAL INHIBITION WITH A FOCUS ON PHOSPHOINOSITIDE-3 KINASE AND IL-2 PARTIAL AGONISTS. FINALLY, WE DISCUSS NOVEL METHODS THAT MAY INCREASE TCF-1(+) POPULATIONS AND THEREFORE IMPROVE IMMUNOTHERAPY RESPONSIVENESS. UNDERSTANDING FEATURES OF AND PATHWAYS TO EXHAUSTION HAS IMPORTANT IMPLICATIONS FOR THE SUCCESS OF IMMUNOTHERAPY, INCLUDING CHECKPOINT BLOCKADE AND ADOPTIVE T-CELL TRANSFER THERAPIES. 2022 16 3895 25 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 17 4434 28 MOLECULAR DISSECTION OF CD8(+) T-CELL DYSFUNCTION. CHRONIC VIRAL INFECTIONS AND CANCER OFTEN LEAD TO THE EMERGENCE OF DYSFUNCTIONAL OR 'EXHAUSTED' CD8(+) T CELLS, AND THE RESTORATION OF THEIR FUNCTIONS IS CURRENTLY THE FOCUS OF THERAPEUTIC INTERVENTIONS. IN THIS REVIEW, WE DETAIL RECENT ADVANCES IN THE ANNOTATION OF THE GENE MODULES AND THE EPIGENETIC LANDSCAPE ASSOCIATED WITH T-CELL DYSFUNCTION. TOGETHER WITH ANALYSIS OF SINGLE-CELL TRANSCRIPTOMES, THESE FINDINGS HAVE ENABLED A DEEPER AND MORE PRECISE UNDERSTANDING OF THE TRANSCRIPTIONAL MECHANISMS THAT INDUCE AND MAINTAIN THE DYSFUNCTIONAL STATE AND HIGHLIGHT THE HETEROGENEITY OF CD8(+) T-CELL PHENOTYPES PRESENT IN CHRONICALLY INFLAMED TISSUE. WE DISCUSS THE RELEVANCE OF THESE FINDINGS FOR UNDERSTANDING THE TRANSCRIPTIONAL AND SPATIAL REGULATION OF DYSFUNCTIONAL T CELLS AND FOR THE DESIGN OF THERAPEUTICS. 2017 18 1054 26 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 19 4049 25 MAKING MEMORIES THAT LAST A LIFETIME: HERITABLE FUNCTIONS OF SELF-RENEWING MEMORY CD8 T CELLS. CLONAL EXPANSION OF VIRUS-SPECIFIC NAIVE T CELLS DURING AN ACUTE VIRAL INFECTION RESULTS IN THE FORMATION OF MEMORY CD8 T CELLS THAT PROVIDE THE HOST WITH LONG-TERM PROTECTIVE IMMUNITY AGAINST THE PATHOGEN. MEMORY CD8 T CELLS DISPLAY ENHANCED EFFECTOR FUNCTIONS COMPARED WITH THEIR NAIVE PRECURSORS, ALLOWING THEM TO RESPOND MORE RAPIDLY AND EFFECTIVELY TO ANTIGEN RE-ENCOUNTER. THE ENHANCED FUNCTIONS OF MEMORY CD8 T CELLS ARE MEDIATED BY HERITABLE CHANGES IN GENE REGULATION. EXPRESSION OF SELECT TRANSCRIPTION FACTORS ALONG WITH LOCUS-SPECIFIC EPIGENETIC MODIFICATIONS ARE COUPLED TO AND ARE ESSENTIAL IN THE FORMATION OF MEMORY-SPECIFIC GENE EXPRESSION PATTERNS. HERE, WE WILL REVIEW THE CHANGES IN GENE EXPRESSION THAT ACCOMPANY DEVELOPMENT OF MEMORY CD8 T CELLS AND DISCUSS CHROMATIN MODIFICATIONS AS A POTENTIAL MEANS FOR HERITABLE PROPAGATION OF THESE CHANGES DURING HOMEOSTATIC CELL DIVISION OF SELF-RENEWING MEMORY CD8 T CELLS. ALSO, WE WILL DISCUSS THERAPIES THAT MANIPULATE HERITABLE GENE REGULATION AS A POTENTIAL MECHANISM TO RESTORE FUNCTION TO NON-FUNCTIONAL MEMORY CD8 T CELLS TO COMBAT CHRONIC VIRAL INFECTION. 2010 20 5414 27 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