4.7 Article

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

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SCIENCE IMMUNOLOGY
卷 2, 期 11, 页码 -

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AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.aai7911

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资金

  1. NIH [CA186866, CA188419, AI070603, AI077283, CA175061, CA208514, UL1 TR001450]
  2. NIH-National Center for Advancing Translational Sciences Grant [TL1 TR001451]
  3. Hollings Cancer Center Cancer Center Support Grant [P30CA138313]

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

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