1 1313 147 DELETING DNMT3A IN CAR T CELLS PREVENTS EXHAUSTION AND ENHANCES ANTITUMOR ACTIVITY. CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL THERAPY IS REVOLUTIONIZING CANCER IMMUNOTHERAPY FOR PATIENTS WITH B CELL MALIGNANCIES AND IS NOW BEING DEVELOPED FOR SOLID TUMORS AND CHRONIC VIRAL INFECTIONS. ALTHOUGH CLINICAL TRIALS HAVE DEMONSTRATED THE CURATIVE POTENTIAL OF CAR T CELL THERAPY, A SUBSTANTIAL AND WELL-ESTABLISHED LIMITATION IS THE HEIGHTENED CONTRACTION AND TRANSIENT PERSISTENCE OF CAR T CELLS DURING PROLONGED ANTIGEN EXPOSURE. THE UNDERLYING MECHANISM(S) FOR THIS DYSFUNCTIONAL STATE, OFTEN TERMED CAR T CELL EXHAUSTION, REMAINS POORLY DEFINED. HERE, WE REPORT THAT EXHAUSTION OF HUMAN CAR T CELLS OCCURS THROUGH AN EPIGENETIC REPRESSION OF THE T CELL'S MULTIPOTENT DEVELOPMENTAL POTENTIAL. DELETION OF THE DE NOVO DNA METHYLTRANSFERASE 3 ALPHA (DNMT3A) IN T CELLS EXPRESSING FIRST- OR SECOND-GENERATION CARS UNIVERSALLY PRESERVED THE CELLS' ABILITY TO PROLIFERATE AND MOUNT AN ANTITUMOR RESPONSE DURING PROLONGED TUMOR EXPOSURE. THE INCREASED FUNCTIONALITY OF THE EXHAUSTION-RESISTANT DNMT3A KNOCKOUT CAR T CELLS WAS COUPLED TO AN UP-REGULATION OF INTERLEUKIN-10, AND GENOME-WIDE DNA METHYLATION PROFILING DEFINED AN ATLAS OF GENES TARGETED FOR EPIGENETIC SILENCING. THIS ATLAS PROVIDES A MOLECULAR DEFINITION OF CAR T CELL EXHAUSTION, WHICH INCLUDES MANY TRANSCRIPTIONAL REGULATORS THAT LIMIT THE "STEMNESS" OF IMMUNE CELLS, INCLUDING CD28, CCR7, TCF7, AND LEF1. LAST, WE DEMONSTRATE THAT THIS EPIGENETICALLY REGULATED MULTIPOTENCY PROGRAM IS FIRMLY COUPLED TO THE CLINICAL OUTCOME OF PRIOR CAR T CELL THERAPIES. THESE DATA DOCUMENT THE CRITICAL ROLE EPIGENETIC MECHANISMS PLAY IN LIMITING THE FATE POTENTIAL OF HUMAN T CELLS AND PROVIDE A ROAD MAP FOR LEVERAGING THIS INFORMATION FOR IMPROVING CAR T CELL EFFICACY. 2021 2 451 39 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 3 2056 27 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 4 1464 34 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 5 6677 37 USING EPIGENETICS TO DEFINE VACCINE-INDUCED MEMORY T CELLS. MEMORY T CELLS GENERATED FROM ACUTE INFECTION OR VACCINATION HAVE THE POTENTIAL TO PROVIDE THE HOST WITH LIFE-LONG IMMUNITY AGAINST RE-INFECTION. PROTECTION BY MEMORY T CELLS IS ACHIEVED THROUGH THEIR ACQUIRED ABILITY TO PERSIST AT ANATOMICAL SITES OF THE PRIMARY INFECTION AS WELL AS MAINTAINING A HEIGHTENED ABILITY TO RECALL EFFECTOR FUNCTIONS. THE MAINTENANCE OF CD8 AND CD4 T CELL FUNCTION IN A STATE OF READINESS IS KEY TO LIFE-LONG IMMUNITY AND MANIFEST THROUGH CHANGES IN TRANSCRIPTIONAL REGULATION. YET, THE ABILITY TO IDENTIFY POISED TRANSCRIPTIONAL PROGRAMS AT THE MAINTENANCE STAGE OF THE RESPONSE IS LACKING FROM MOST TRANSCRIPTIONAL PROFILING STUDIES OF MEMORY T CELLS. EPIGENETIC PROFILING ALLOWS FOR THE ASSESSMENT OF TRANSCRIPTIONALLY POISED (PROMOTERS THAT ARE READILY ACCESSIBLE FOR TRANSCRIPTION) STATES OF ANTIGEN-SPECIFIC T CELLS WITHOUT MANIPULATION OF THE ACTIVATION STATE OF THE CELL. HERE WE REVIEW RECENT STUDIES THAT HAVE EXAMINED EPIGENETIC PROGRAMS OF EFFECTOR AND MEMORY T CELL SUBSETS. THESE REPORTS DEMONSTRATE THAT ACQUISITION OF EPIGENETIC PROGRAMS DURING MEMORY T CELL DIFFERENTIATION TO ACUTE AND CHRONIC INFECTIONS IS COUPLED TO, AND POTENTIALLY REGULATE, THE CELL'S RECALL RESPONSE. WE DISCUSS THE USEFULNESS OF EPIGENETIC PROFILING IN CHARACTERIZING T CELL DIFFERENTIATION STATE AND FUNCTION FOR PRECLINICAL EVALUATION OF VACCINES AND THE CURRENT METHODOLOGIES FOR SINGLE LOCUS VERSUS GENOME-WIDE EPIGENETIC PROFILING. 2013 6 6060 44 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 7 6851 38 [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 8 5900 39 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 9 6014 26 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 10 2718 36 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 2145 35 EPIGENETIC MAINTENANCE OF ACQUIRED GENE EXPRESSION PROGRAMS DURING MEMORY CD8 T CELL HOMEOSTASIS. MEMORY CD8 T CELLS HAVE A UNIQUE ABILITY TO PROVIDE LIFELONG IMMUNITY AGAINST PATHOGENS CONTAINING THEIR COGNATE EPITOPE. BECAUSE OF THEIR ABILITY TO PROVIDE LIFELONG PROTECTION, THE GENERATION OF MEMORY T CELLS IS NOW A MAJOR FOCUS FOR CURRENT VACCINATION OR ADOPTIVE CELL THERAPY APPROACHES TO TREAT CHRONIC VIRAL INFECTIONS AND CANCER. IT IS NOW CLEAR THAT MAINTENANCE OF MEMORY CD8 T CELLS OCCURS THROUGH A PROCESS OF ANTIGEN-INDEPENDENT HOMEOSTATIC PROLIFERATION, WHICH IS REGULATED IN PART BY THE GAMMA CHAIN CYTOKINES IL-7 AND IL-15. HERE, WE WILL DESCRIBE THE ROLE OF THESE CYTOKINES IN THE SURVIVAL AND SELF-RENEWAL OF MEMORY CD8 T CELLS. FURTHER, WE WILL DESCRIBE THE ROLE OF EPIGENETICS IN THE MAINTENANCE OF ACQUIRED FUNCTIONS AMONG MEMORY CD8 T CELLS DURING HOMEOSTATIC PROLIFERATION. 2018 12 5414 30 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 13 2831 47 FOCUS ON T CELL EXHAUSTION: NEW ADVANCES IN TRADITIONAL CHINESE MEDICINE IN INFECTION AND CANCER. IN CHRONIC INFECTIONS AND CANCERS, T LYMPHOCYTES (T CELLS) ARE EXPOSED TO PERSISTENT ANTIGEN OR INFLAMMATORY SIGNALS. THE CONDITION IS OFTEN ASSOCIATED WITH A DECLINE IN T-CELL FUNCTION: A STATE CALLED "EXHAUSTION". T CELL EXHAUSTION IS A STATE OF T CELL DYSFUNCTION CHARACTERIZED BY INCREASED EXPRESSION OF A SERIES OF INHIBITORY RECEPTORS (IRS), DECREASED EFFECTOR FUNCTION, AND DECREASED CYTOKINE SECRETION, ACCOMPANIED BY TRANSCRIPTIONAL AND EPIGENETIC CHANGES AND METABOLIC DEFECTS. THE RISE OF IMMUNOTHERAPY, PARTICULARLY THE USE OF IMMUNE CHECKPOINT INHIBITORS (ICIS), HAS DRAMATICALLY CHANGED THE CLINICAL TREATMENT PARADIGM FOR PATIENTS. HOWEVER, ITS LOW RESPONSE RATE, SINGLE TARGET AND HIGH IMMUNOTOXICITY LIMIT ITS CLINICAL APPLICATION. THE MULTIPLE IMMUNOMODULATORY POTENTIAL OF TRADITIONAL CHINESE MEDICINE (TCM) PROVIDES A NEW DIRECTION FOR IMPROVING THE TREATMENT OF T CELL EXHAUSTION. HERE, WE REVIEW RECENT ADVANCES THAT HAVE PROVIDED A CLEARER MOLECULAR UNDERSTANDING OF T CELL EXHAUSTION, REVEALING THE CHARACTERISTICS AND CAUSES OF T CELL EXHAUSTION IN PERSISTENT INFECTIONS AND CANCERS. IN ADDITION, THIS PAPER SUMMARIZES RECENT ADVANCES IN IMPROVING T CELL EXHAUSTION IN INFECTIOUS DISEASES AND CANCER WITH THE AIM OF PROVIDING A COMPREHENSIVE AND VALUABLE SOURCE OF INFORMATION ON TCM AS AN EXPERIMENTAL STUDY AND THEIR ROLE IN COLLABORATION WITH ICIS THERAPY. 2023 14 1462 43 DISRUPTION OF TET2 PROMOTES THE THERAPEUTIC EFFICACY OF CD19-TARGETED T CELLS. CANCER IMMUNOTHERAPY BASED ON GENETICALLY REDIRECTING T CELLS HAS BEEN USED SUCCESSFULLY TO TREAT B CELL MALIGNANCIES(1-3). IN THIS STRATEGY, THE T CELL GENOME IS MODIFIED BY INTEGRATION OF VIRAL VECTORS OR TRANSPOSONS ENCODING CHIMAERIC ANTIGEN RECEPTORS (CARS) THAT DIRECT TUMOUR CELL KILLING. HOWEVER, THIS APPROACH IS OFTEN LIMITED BY THE EXTENT OF EXPANSION AND PERSISTENCE OF CAR T CELLS(4,5). HERE WE REPORT MECHANISTIC INSIGHTS FROM STUDIES OF A PATIENT WITH CHRONIC LYMPHOCYTIC LEUKAEMIA TREATED WITH CAR T CELLS TARGETING THE CD19 PROTEIN. FOLLOWING INFUSION OF CAR T CELLS, ANTI-TUMOUR ACTIVITY WAS EVIDENT IN THE PERIPHERAL BLOOD, LYMPH NODES AND BONE MARROW; THIS ACTIVITY WAS ACCOMPANIED BY COMPLETE REMISSION. UNEXPECTEDLY, AT THE PEAK OF THE RESPONSE, 94% OF CAR T CELLS ORIGINATED FROM A SINGLE CLONE IN WHICH LENTIVIRAL VECTOR-MEDIATED INSERTION OF THE CAR TRANSGENE DISRUPTED THE METHYLCYTOSINE DIOXYGENASE TET2 GENE. FURTHER ANALYSIS REVEALED A HYPOMORPHIC MUTATION IN THIS PATIENT'S SECOND TET2 ALLELE. TET2-DISRUPTED CAR T CELLS EXHIBITED AN EPIGENETIC PROFILE CONSISTENT WITH ALTERED T CELL DIFFERENTIATION AND, AT THE PEAK OF EXPANSION, DISPLAYED A CENTRAL MEMORY PHENOTYPE. EXPERIMENTAL KNOCKDOWN OF TET2 RECAPITULATED THE POTENCY-ENHANCING EFFECT OF TET2 DYSFUNCTION IN THIS PATIENT'S CAR T CELLS. THESE FINDINGS SUGGEST THAT THE PROGENY OF A SINGLE CAR T CELL INDUCED LEUKAEMIA REMISSION AND THAT TET2 MODIFICATION MAY BE USEFUL FOR IMPROVING IMMUNOTHERAPIES. 2018 15 2367 38 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 16 4434 32 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 17 6365 30 THE ROLE OF METABOLIC DYSFUNCTION IN T-CELL EXHAUSTION DURING CHRONIC VIRAL INFECTION. T CELLS ARE IMPORTANT COMPONENTS OF ADAPTIVE IMMUNITY THAT PROTECT THE HOST AGAINST INVADING PATHOGENS DURING INFECTION. UPON RECOGNIZING THE ACTIVATION SIGNALS, NAIVE AND/OR MEMORY T CELLS WILL INITIATE CLONAL EXPANSION, TRIGGER DIFFERENTIATION INTO EFFECTOR POPULATIONS AND TRAFFIC TO THE INFLAMED SITES TO ELIMINATE PATHOGENS. HOWEVER, IN CHRONIC VIRAL INFECTIONS, SUCH AS THOSE CAUSED BY HUMAN IMMUNODEFICIENCY VIRUS (HIV), HEPATITIS B AND C (HBV AND HCV), T CELLS EXHIBIT IMPAIRED FUNCTION AND BECOME DIFFICULT TO CLEAR PATHOGENS IN A STATE KNOWN AS T-CELL EXHAUSTION. THE ACTIVATION AND FUNCTION PERSISTENCE OF T CELLS DEMAND FOR DYNAMIC CHANGES IN CELLULAR METABOLISM TO MEET THEIR BIOENERGETIC AND BIOSYNTHETIC DEMANDS, ESPECIALLY THE AUGMENTATION OF AEROBIC GLYCOLYSIS, WHICH NOT ONLY PROVIDE EFFICIENT ENERGY GENERATION, BUT ALSO FUEL MULTIPLE BIOCHEMICAL INTERMEDIATES THAT ARE ESSENTIAL FOR NUCLEOTIDE, AMINO ACID, FATTY ACID SYNTHESIS AND MITOCHONDRIA FUNCTION. CHANGES IN CELLULAR METABOLISM ALSO AFFECT THE FUNCTION OF EFFECTORS T CELLS THROUGH MODIFYING EPIGENETIC SIGNATURES. IT IS WIDELY ACCEPTED THAT THE DYSFUNCTION OF T CELL METABOLISM CONTRIBUTES GREATLY TO T-CELL EXHAUSTION. HERE, WE REVIEWED RECENT FINDINGS ON T CELLS METABOLISM UNDER CHRONIC VIRAL INFECTION, SEEKING TO REVEAL THE ROLE OF METABOLIC DYSFUNCTION PLAYED IN T-CELL EXHAUSTION. 2022 18 3895 32 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 19 4340 31 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 20 4049 34 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