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Tissues are exposed to diverse inflammatory challenges that shape future inflammatory responses. While cellular metabolism regulates immune function, how metabolism programs and stabilizes immune states within tissues and tunes susceptibility to inflammation is poorly understood. Here, we describe an innate immune metabolic switch that programs long-term intestinal tolerance. Intestinal interleukin-18 (IL-18) stimulation elicited tolerogenic macrophages by preventing their proinflammatory glycolytic polarization via metabolic reprogramming to fatty acid oxidation (FAO). FAO reprogramming was triggered by IL-18 activation of SLC12A3 (NCC), leading to sodium influx, release of mitochondrial DNA, and activation of stimulator of interferon genes (STING). FAO was maintained in macrophages by a bistable switch that encoded memory of IL-18 stimulation and by intercellular positive feedback that sustained the production of macrophage-derived 2'3'-cyclic GMP-AMP (cGAMP) and epithelial-derived IL-18. Thus, a tissue-reinforced metabolic switch encodes durable immune tolerance in the gut and may enable reconstructing compromised immune tolerance in chronic inflammation., Competing Interests: Declaration of interests The authors declare no competing financial interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

CD8 + T cells must persist and function in diverse tumor microenvironments to exert their effects. Thus, understanding common underlying expression programs could better inform the next generation of immunotherapies. We apply a generalizable matrix factorization algorithm that recovers both shared and context-specific expression programs from diverse datasets to a single-cell RNA sequencing (scRNA-seq) compendium of 33,161 CD8 + T cells from 132 patients with seven human cancers. Our meta-single-cell analyses uncover a pan-cancer T cell dysfunction program that predicts clinical non-response to checkpoint blockade in melanoma and highlights CXCR6 as a pan-cancer marker of chronically activated T cells. Cxcr6 is trans-activated by AP-1 and repressed by TCF1. Using mouse models, we show that Cxcr6 deletion in CD8 + T cells increases apoptosis of PD1 + TIM3 + cells, dampens CD28 signaling, and compromises tumor growth control. Our study uncovers a TCF1:CXCR6 axis that counterbalances PD1-mediated suppression of CD8 + cell responses and is essential for effective anti-tumor immunity., Competing Interests: Declaration of interests A.C.A. is a member of the SAB for Tizona Therapeutics, Trishula Therapeutics, Compass Therapeutics, ExcepGen, and Zumutor Biologics, which have interests in cancer immunotherapy. A.C.A. is also a paid consultant for iTeos Therapeutics and Larkspur Biosciences. A.C.A.’s interests were reviewed and managed by the Brigham and Women’s Hospital and Partners Healthcare in accordance with their conflict-of-interest policies. O.R.-R. is an employee of Genentech. A.R. is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas, and was an SAB member of Thermo Fisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics, and Asimov. From August 1, 2020, A.R. is an employee of Genentech and has equity in Roche. When at the Broad, A.R.’s interests were reviewed and managed by the Broad Institute, MIT and HHMI in accordance with their conflict-of-interest policies. A provisional patent application was filed including work in this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Gut inflammation involves contributions from immune and non-immune cells, whose interactions are shaped by the spatial organization of the healthy gut and its remodeling during inflammation. The crosstalk between fibroblasts and immune cells is an important axis in this process, but our understanding has been challenged by incomplete cell-type definition and biogeography. To address this challenge, we used multiplexed error-robust fluorescence in situ hybridization (MERFISH) to profile the expression of 940 genes in 1.35 million cells imaged across the onset and recovery from a mouse colitis model. We identified diverse cell populations, charted their spatial organization, and revealed their polarization or recruitment in inflammation. We found a staged progression of inflammation-associated tissue neighborhoods defined, in part, by multiple inflammation-associated fibroblasts, with unique expression profiles, spatial localization, cell-cell interactions, and healthy fibroblast origins. Similar signatures in ulcerative colitis suggest conserved human processes. Broadly, we provide a framework for understanding inflammation-induced remodeling in the gut and other tissues., Competing Interests: Declaration of interests J.R.M. is a co-founder of, stakeholder in, and advisor for Vizgen, Inc. J.R.M. is an inventor on patents associated with MERFISH applied for on his behalf by Harvard University and Boston Children’s Hospital. J.R.M.’s interests were reviewed and are managed by Boston Children’s Hospital in accordance with their conflict-of-interest policies. R.N. is a paid consultant for Quris-AI. V.K.K. has an ownership interest in Tizona Therapeutics, Trishula Therapeutics, Celsius Therapeutics, Bicara Therapeutics, Larkspur Therapeutics. V.K.K. has financial interests in Biocon Biologic, Compass, Elpiscience Biopharmaceutical Ltd, Equilium Inc, PerkinElmer, and Syngene Intl. V.K.K. is a member of SABs for Cell Signaling Technology, Elpiscience Biopharmaceutical Ltd, GlaxoSmithKline, Larkspur, Novartis Sabatolimab, Tizona Therapeutics, Tr1X, and Werewolf. A.C.A. is a member of the SAB for Tizona Therapeutics, Trishula Therapeutics, Compass Therapeutics, Zumutor Biologics, ImmuneOncia, and Nekonal Sarl. A.C.A. is also a paid consultant for iTeos Therapeutics, Larkspur Biosciences, and Excepgen. R.N., V.K.K., and A.C.A.’s interests were reviewed and managed by Mass General Brigham in accordance with their conflict-of-interest policies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Stem-like CD8 + T cells are regulated by T cell factor 1 (TCF1) and are considered requisite for immune checkpoint blockade (ICB) response. However, recent findings indicate that reliance on TCF1 + CD8 + T cells for ICB efficacy may differ across tumor contexts. We find that TCF1 is essential for optimal priming of tumor antigen-specific CD8 + T cells and ICB response in poorly immunogenic tumors that accumulate TOX + dysfunctional T cells, but is dispensable for T cell priming and therapy response in highly immunogenic tumors that efficiently expand transitory effectors. Importantly, improving T cell priming by vaccination or by enhancing antigen presentation on tumors rescues the defective responses of TCF1-deficient CD8 + T cells upon ICB in poorly immunogenic tumors. Our study highlights TCF1's role during the early stages of anti-tumor CD8 + T cell responses with important implications for guiding optimal therapeutic interventions in cancers with low TCF1 + CD8 + T cells and low-neo-antigen expression., Competing Interests: Declaration of interests A.C.A. is a member of the SAB for Tizona Therapeutics, Trishula Therapeutics, Compass Therapeutics, Zumutor Biologics, ImmuneOncia, and Excepgen, which have interests in cancer immunotherapy. A.C.A. is a paid consultant for iTeos Therapeutics and Larkspur Biosciences. A.C.A.’s interests were reviewed and managed by the Brigham and Women’s Hospital. C.M.J. is an employee of the VA Maryland Health Care System. The views reported here do not reflect the views of the VA or United States Government. C.M.J. has an equity position with Cartesian Therapeutics. L.B. is also an employee of SANA Biotechnology, Inc. Neither SANA Biotechnology nor its subsidiaries have conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The immune system plays critical roles in both autoimmunity and cancer, diseases at opposite ends of the immune spectrum. Autoimmunity arises from loss of T cell tolerance against self, while in cancer, poor immunity against transformed self fails to control tumor growth. Blockade of pathways that preserve self-tolerance is being leveraged to unleash immunity against many tumors; however, widespread success is hindered by the autoimmune-like toxicities that arise in treated patients. Knowledge gained from the treatment of autoimmunity can be leveraged to treat these toxicities in patients. Further, the understanding of how T cell dysfunction arises in cancer can be leveraged to induce a similar state in autoreactive T cells. Here, we review what is known about the T cell response in autoimmunity and cancer and highlight ways in which we can learn from the nexus of these two diseases to improve the application, efficacy, and management of immunotherapies., Competing Interests: Declaration of interests A.C.A. is a member of the SAB for Tizona Therapeutics, Trishula Therapeutics, Compass Therapeutics, Zumutor Biologics, ImmuneOncia, and Nekonal Sarl. A.C.A. is also a paid consultant for iTeos Therapeutics, Larkspur Biosciences, and Excepgen. A.C.A.’s interests were reviewed and managed by the Brigham and Women’s Hospital and Partners Healthcare in accordance with their conflict-of-interest policies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Identifying signals in the tumor microenvironment (TME) that shape CD8 + T cell phenotype can inform novel therapeutic approaches for cancer. Here, we identified a gradient of increasing glucocorticoid receptor (GR) expression and signaling from naïve to dysfunctional CD8 + tumor-infiltrating lymphocytes (TILs). Conditional deletion of the GR in CD8 + TILs improved effector differentiation, reduced expression of the transcription factor TCF-1, and inhibited the dysfunctional phenotype, culminating in tumor growth inhibition. GR signaling transactivated the expression of multiple checkpoint receptors and promoted the induction of dysfunction-associated genes upon T cell activation. In the TME, monocyte-macrophage lineage cells produced glucocorticoids and genetic ablation of steroidogenesis in these cells as well as localized pharmacologic inhibition of glucocorticoid biosynthesis improved tumor growth control. Active glucocorticoid signaling associated with failure to respond to checkpoint blockade in both preclinical models and melanoma patients. Thus, endogenous steroid hormone signaling in CD8 + TILs promotes dysfunction, with important implications for cancer immunotherapy., Competing Interests: Declaration of Interests A.C.A. is a member of the SAB for Tizona Therapeutics, Compass Therapeutics, Zumutor Biologics, and Astellas Global Pharma Development, which have interests in cancer immunotherapy. V.K.K. is a member of the SAB for Astellas Global Pharma Development and has an ownership interest and is a member of the SAB for Tizona Therapeutics. A.R. and V.K.K. are co-founders of and have an ownership interest in Celsius Therapeutics. A.C.A.’s and V.K.K.’s interests were reviewed and managed by the Brigham and Women’s Hospital and Partners Healthcare in accordance with their conflict of interest policies. M.B. is a consultant for Eli Lilly and Company. A.R. is also an SAB member for Thermo Fisher, Neogene Therapeutics, Asimov, and Syros Pharmaceuticals and is an equity holder in Immunitas. A.R.’s interests were reviewed and managed by the Broad Institute and HHMI in accordance with their conflict of interest policies. A provisional patent application was filed including work in this manuscript., (Copyright © 2020 Elsevier Inc. All rights reserved.)