Rachidi et al. demonstrate that platelets blocked CD4+ and CD8+ T cell function in vitro and in vivo by the release of functional TGFβ (from its platelet-intrinsic cell surface docking receptor, GARP) and, to a lesser degree, by release of lactate. Platelet-specific genetic knockout of GARP or gp96 (which is required for GARP expression) or the addition of antiplatelet agents all significantly improved the efficacy of T cell therapy in murine tumor models.
Cancer-associated thrombocytosis has long been linked to poor clinical outcome, but the underlying mechanism is enigmatic. We hypothesized that platelets promote malignancy and resistance to therapy by dampening host immunity. We show that genetic targeting of platelets enhances adoptive T cell therapy of cancer. An unbiased biochemical and structural biology approach established transforming growth factor beta (TGFbeta) and lactate as major platelet-derived soluble factors to obliterate CD4+ and CD8+ T cell functions. Moreover, we found that platelets are the dominant source of functional TGFbeta systemically as well as in the tumor microenvironment through constitutive expression of the TGFbeta-docking receptor glycoprotein A repetitions predominant (GARP) rather than secretion of TGFbeta per se. Platelet-specific deletion of the GARP-encoding gene Lrrc32 blunted TGFbeta activity at the tumor site and potentiated protective immunity against both melanoma and colon cancer. Last, this study shows that T cell therapy of cancer can be substantially improved by concurrent treatment with readily available antiplatelet agents. We conclude that platelets constrain T cell immunity through a GARP-TGFbeta axis and suggest a combination of immunotherapy and platelet inhibitors as a therapeutic strategy against cancer.
Author Info: (1) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. Hollings Cancer Center, Medical University of South Carolina, Charle
Author Info: (1) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (2) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (3) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (4) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (5) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (6) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (7) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA. (8) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA. (9) Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA. (10) Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA. (11) National Institutes of Standards and Technology, Hollings Marine Laboratory, Charleston, SC 29412, USA. (12) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (13) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. (14) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. zihai@musc.edu. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. First Affiliated Hospital, Zhengzhou University School of Medicine, Zhengzhou 450052, Henan, China.
