Multiomics analysis of CD8+ T cells in “supportive niches”, like melanoma and lung cancer, exhibited features of tumor reactivity-driven exhaustion, including TEM phenotypes, expanded TCRs, and T cell-activating cancer-related (neo)antigens. Meanwhile, CD8+ T cells in “non-supportive niches”, like glioblastoma (GBM), exhibited features of an insufficiently activated, hypofunctional, antiproliferative state, including non-expanded TCRs, high T cell-recognizable self epitopes, and wound healing signatures. Anti-PD-1 facilitated these tolerogenic features, while DC vaccines partly corrected them, inducing TEM CD8+ T cells and antigen-specific immunity in GBM.
Contributed by Lauren Hitchings
ABSTRACT: Clinically relevant immunological biomarkers that discriminate between diverse hypofunctional states of tumor-associated CD8(+) T cells remain disputed. Using multiomics analysis of CD8(+) T cell features across multiple patient cohorts and tumor types, we identified tumor niche-dependent exhausted and other types of hypofunctional CD8(+) T cell states. CD8(+) T cells in "supportive" niches, like melanoma or lung cancer, exhibited features of tumor reactivity-driven exhaustion (CD8(+) T(EX)). These included a proficient effector memory phenotype, an expanded T cell receptor (TCR) repertoire linked to effector exhaustion signaling, and a cancer-relevant T cell-activating immunopeptidome composed of largely shared cancer antigens or neoantigens. In contrast, "nonsupportive" niches, like glioblastoma, were enriched for features of hypofunctionality distinct from canonical exhaustion. This included immature or insufficiently activated T cell states, high wound healing signatures, nonexpanded TCR repertoires linked to anti-inflammatory signaling, high T cell-recognizable self-epitopes, and an antiproliferative state linked to stress or prodeath responses. In situ spatial mapping of glioblastoma highlighted the prevalence of dysfunctional CD4(+):CD8(+) T cell interactions, whereas ex vivo single-cell secretome mapping of glioblastoma CD8(+) T cells confirmed negligible effector functionality and a promyeloid, wound healing-like chemokine profile. Within immuno-oncology clinical trials, anti-programmed cell death protein 1 (PD-1) immunotherapy facilitated glioblastoma's tolerogenic disparities, whereas dendritic cell (DC) vaccines partly corrected them. Accordingly, recipients of a DC vaccine for glioblastoma had high effector memory CD8(+) T cells and evidence of antigen-specific immunity. Collectively, we provide an atlas for assessing different CD8(+) T cell hypofunctional states in immunogenic versus nonimmunogenic cancers.
Author Info: (1) Laboratory of Cell Stress & Immunity, Department of Cellular and Molecular Medicine, KU Leuven, Leuven 3000, Belgium. Ludwig Institute for Cancer Research, Brussels 1200, Belgi
Author Info: (1) Laboratory of Cell Stress & Immunity, Department of Cellular and Molecular Medicine, KU Leuven, Leuven 3000, Belgium. Ludwig Institute for Cancer Research, Brussels 1200, Belgium. Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX1 4BH, UK. De Duve Institute, UCLouvain, Brussels 1200, Belgium. (2) Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich Heine University Hospital, Dsseldorf 40225, Germany. (3) Laboratory of Cell Stress & Immunity, Department of Cellular and Molecular Medicine, KU Leuven, Leuven 3000, Belgium. (4) Laboratory for Precision Cancer Medicine, Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven 3000, Belgium. (5) Laboratory for Precision Cancer Medicine, Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven 3000, Belgium. (6) Laboratory of Cell Stress & Immunity, Department of Cellular and Molecular Medicine, KU Leuven, Leuven 3000, Belgium. (7) Laboratory of Cell Stress & Immunity, Department of Cellular and Molecular Medicine, KU Leuven, Leuven 3000, Belgium. (8) Laboratory of Cell Stress & Immunity, Department of Cellular and Molecular Medicine, KU Leuven, Leuven 3000, Belgium. (9) Laboratory of Cell Stress & Immunity, Department of Cellular and Molecular Medicine, KU Leuven, Leuven 3000, Belgium. (10) Laboratory for Precision Cancer Medicine, Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven 3000, Belgium. (11) Laboratory for Precision Cancer Medicine, Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven 3000, Belgium. (12) Department of Neurosurgery, Medical Faculty, Heinrich Heine University Hospital, Dsseldorf 40225, Germany. (13) Department of Neurosurgery, Medical Faculty, Heinrich Heine University Hospital, Dsseldorf 40225, Germany. (14) IsoPlexis Corporation, Branford, CT 06405-2801, USA. (15) IsoPlexis Corporation, Branford, CT 06405-2801, USA. (16) Laboratory of Experimental Oncology, Department of Oncology, KU Leuven and Department of General Medical Oncology, UZ Leuven, Leuven 3000, Belgium. (17) Laboratory of Dynamics in Biological Systems, Department of Cellular and Molecular Medicine, KU Leuven, Leuven 3000, Belgium. (18) Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium. VIB Center for Cancer Biology, VIB, Leuven 3000, Belgium. (19) Department of Cellular and Molecular Medicine, KU Leuven, Leuven 3000, Belgium. (20) Laboratory of Experimental Oncology, Department of Oncology, KU Leuven and Department of General Medical Oncology, UZ Leuven, Leuven 3000, Belgium. (21) Laboratory of Tumor Microenvironment and Therapeutic Resistance, Department of Oncology, VIB Center for Cancer Biology, KU Leuven, Leuven 3000, Belgium. Department of Neurological Surgery, UCSF Comprehensive Cancer Center, UCSF, San Francisco, CA 94143-0350, USA. (22) VIB Center for Brain and Disease Research, Leuven 3000, Belgium. Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven 3000, Belgium. Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge CB22 3AT, UK. (23) Department of Neurosurgery, University Hospitals Leuven, Leuven 3000, Belgium. Laboratory of Experimental Neurosurgery and Neuroanatomy, Department of Neurosciences, KU Leuven, Leuven 3000, Belgium. Leuven Brain Institute (LBI), Leuven 3000, Belgium. (24) Ludwig Institute for Cancer Research, Brussels 1200, Belgium. Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX1 4BH, UK. De Duve Institute, UCLouvain, Brussels 1200, Belgium. (25) Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium. VIB Center for Cancer Biology, VIB, Leuven 3000, Belgium. (26) Neurosurgery Department, Europaziekenhuizen - Cliniques de l'Europe, Sint-Elisabeth, Brussels 1180, Belgium. (27) Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven 3000, Belgium. (28) Laboratory for Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven 3000, Belgium. (29) Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden 2333 ZA, Netherlands. (30) Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich Heine University Hospital, Dsseldorf 40225, Germany. (31) Laboratory for Precision Cancer Medicine, Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven 3000, Belgium. (32) Laboratory of Cell Stress & Immunity, Department of Cellular and Molecular Medicine, KU Leuven, Leuven 3000, Belgium.
