Weng et al. focused on unexplored mechanisms that contribute to T cell exhaustion. They observed that CD47, upregulated on human and murine tumor-infiltrating exhausted CD8+ T cells, bound matrix protein thrombospondin (TSP-1) to promote exhaustion. Mechanistically, TSP-1–CD47 binding activated calcineurin-NFAT signaling, resulting in TOX induction, inhibitory receptor expression (PD-1, TIM-3 and LAG-3) and decreased effector levels (TNFα and IFNγ), inducing CD8+ T cell exhaustion and tumor progression. Disrupting the TSP-1–CD47 interaction prevented T cell exhaustion, restored T cell function, and enhanced anti-PD-1 therapy.
Contributed by Katherine Turner
ABSTRACT: T cell exhaustion is a major barrier to effective cancer immunotherapy. Although immune checkpoint blockade can reinvigorate exhausted T cells, not all patients achieve long-term responses, partly due to the refractory nature of terminally exhausted T cells. Beyond persistent antigen stimulation, the environmental drivers of exhaustion remain to be thoroughly characterized. Here we identify CD47 upregulation in tumor-infiltrating exhausted CD8(+) T cells in both human and murine tumors. We reveal a novel role for the extracellular matrix protein thrombospondin-1 (TSP-1) in engaging CD47 on T cells to promote exhaustion. This interaction activates calcineurin-NFAT signaling, inducing upregulation of TOX and expression of inhibitory receptors, and impairing effector function during tumor progression. Importantly, disrupting the TSP-1-CD47 axis prevents T cell exhaustion and enhances tumor control. Our findings identify a novel pathway promoting T cell dysfunction and suggest that targeting the TSP-1-CD47 axis is a promising strategy to enhance T cell immunity and immunotherapy efficacy.
Author Info: (1) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cor
Author Info: (1) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (2) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (3) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (4) Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Department of Biomedicine, University of Basel, Basel, Switzerland. (5) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (6) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (7) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (8) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (9) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (10) Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, The Rockefeller University, Weill Cornell Medicine, New York, NY, USA. (11) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (12) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (13) Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Icahn School of Medicine at Mount Sinai, New York, NY, USA. (14) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (15) Memorial Sloan-Kettering Cancer Center, New York, NY, USA. (16) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (17) Memorial Sloan-Kettering Cancer Center, New York, NY, USA. (18) Memorial Sloan-Kettering Cancer Center, New York, NY, USA. (19) Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Department of Medicine at Weill Cornell Medicine, New York, NY, USA. Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School, New York, NY, USA. (20) Surface Oncology Inc., Cambridge, MA, USA. InduPro, Seattle, WA, USA. (21) Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Department of Dermatology, Weill Cornell Medicine, New York, NY, USA. Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA. (22) Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (23) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. jwolchok@med.cornell.edu. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. jwolchok@med.cornell.edu. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. jwolchok@med.cornell.edu. Department of Medicine at Weill Cornell Medicine, New York, NY, USA. jwolchok@med.cornell.edu. Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School, New York, NY, USA. jwolchok@med.cornell.edu. (24) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. tmerghoub@med.cornell.edu. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. tmerghoub@med.cornell.edu. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. tmerghoub@med.cornell.edu.
