Acharya and Madi et al. describe how glucocorticoid signaling in the tumor microenvironment is associated with dysfunctional tumor-infiltrating CD8+ T cells. By deleting the gene expression of the glucocorticoid receptor in T cells, they show improved tumor control and decreased immune checkpoint expression. The primary source of glucocorticoid production in the tumor environment was found to be tumor-associated myeloid cells. Glucocorticoid production resulted in increased checkpoint expression on CD8+ T cells and reduced their capacity to produce pro-inflammatory cytokines, leaving these cells in a dysfunctional state and inhibiting checkpoint inhibition therapy efficacy.
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ABSTRACT: 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.
Author Info: (1) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. (2) Ev
Author Info: (1) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. (2) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. (3) Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. (4) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (5) Departments of Dermatology, Pathology, and Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA. (6) Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 01225, USA. (7) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Immunology, Harvard Medical School, Boston, MA02115, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (8) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (9) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Department of Biology, Koch Institute and Ludwig Center, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: aregev@broadinstitute.org. (10) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: vkuchroo@evergrande.hms.harvard.edu. (11) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: acanderson@bwh.harvard.edu.
