Research ArticleIMMUNOTHERAPY

Platelets subvert T cell immunity against cancer via GARP-TGFβ axis

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Science Immunology  05 May 2017:
Vol. 2, Issue 11, eaai7911
DOI: 10.1126/sciimmunol.aai7911

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Cancer immunotherapy according to GARP

Cancer, like microbes, can adapt to a single therapy, making combination therapies the approach of choice. Complementary therapies that decrease immunosuppression may boost the efficacy of immunotherapies. Now, Rachidi et al. report that targeting platelets improves adoptive T cell therapy of multiple cancers in mice. They found that transforming growth factor β (TGFβ) from platelets decrease T cell function largely through the expression of the TGFβ-docking receptor glycoprotein A repetitions predominant (GARP). These data suggest that combining immunotherapy with platelet inhibitors may be a complementary approach to cancer therapy.

Abstract

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 β (TGFβ) 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 TGFβ systemically as well as in the tumor microenvironment through constitutive expression of the TGFβ-docking receptor glycoprotein A repetitions predominant (GARP) rather than secretion of TGFβ per se. Platelet-specific deletion of the GARP-encoding gene Lrrc32 blunted TGFβ 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-TGFβ axis and suggest a combination of immunotherapy and platelet inhibitors as a therapeutic strategy against cancer.

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