Vignali et al. investigated the suppressive mechanisms used by abundant checkpoint inhibitor-resistant exhausted CD8+ T cells in the TME. The most terminally exhausted intratumoral CD8+ T cells (tTex) shared transcriptional and functional similarities with CD4+Foxp3+ Tregs and were capable of directly suppressing T cell proliferation ex vivo. Mechanistically, tTex suppression required CD39, which was induced on tTex cells by tumor hypoxia; suppression could be reversed by deletion of CD39 in CD8+ T cells or by treatment with tumor hypoxia-targeting treatments, resulting in slower tumor progression and improved responsiveness to checkpoint inhibitors.
Contributed by Katherine Turner
ABSTRACT: CD8(+) T cells are critical for elimination of cancer cells. Factors within the tumor microenvironment (TME) can drive these cells to a hypofunctional state known as exhaustion. The most terminally exhausted T (tT(ex)) cells are resistant to checkpoint blockade immunotherapy and might instead limit immunotherapeutic efficacy. Here we show that intratumoral CD8(+) tT(ex) cells possess transcriptional features of CD4(+)Foxp3(+) regulatory T cells and are similarly capable of directly suppressing T cell proliferation ex vivo. tT(ex) cell suppression requires CD39, which generates immunosuppressive adenosine. Restricted deletion of CD39 in endogenous CD8(+) T cells resulted in slowed tumor progression, improved immunotherapy responsiveness and enhanced infiltration of transferred tumor-specific T cells. CD39 is induced on tT(ex) cells by tumor hypoxia, thus mitigation of hypoxia limits tT(ex) suppression. Together, these data suggest tT(ex) cells are an important regulatory population in cancer and strategies to limit their generation, reprogram their immunosuppressive state or remove them from the TME might potentiate immunotherapy.
Author Info: (1) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsbur
Author Info: (1) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA. (2) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA. (3) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA. (4) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA. (5) Division of Pediatric Rheumatology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA. (6) Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. (7) Tumor Microenvironment Center, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA. (8) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA. (9) Tumor Microenvironment Center, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA. (10) Center for Inflammation Research, Department of Anesthesia, Critical Care & Pain Medicine and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. (11) Division of Pediatric Rheumatology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA. (12) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA. (13) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. gdelgoffe@pitt.edu. Tumor Microenvironment Center, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA. gdelgoffe@pitt.edu.
