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

被引:282
作者
Rachidi, Saleh [1 ,2 ]
Metelli, Alessandra [1 ,2 ]
Riesenberg, Brian [1 ,2 ]
Wu, Bill X. [1 ,2 ]
Nelson, Michelle H. [1 ,2 ]
Wallace, Caroline [1 ,2 ]
Paulos, Chrystal M. [1 ,2 ,3 ]
Rubinstein, Mark P. [1 ,2 ,3 ]
Garrett-Mayer, Elizabeth [2 ,4 ]
Hennig, Mirko [5 ]
Bearden, Daniel W. [6 ]
Yang, Yi [1 ,2 ]
Liu, Bei [1 ,2 ]
Li, Zihai [1 ,2 ,7 ]
机构
[1] Med Univ South Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA
[2] Med Univ South Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA
[3] Med Univ South Carolina, Dept Surg, Charleston, SC 29425 USA
[4] Med Univ South Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA
[5] Med Univ South Carolina, Dept Biochem & Mol Bio, Charleston, SC 29425 USA
[6] NIST, Hollings Marine Lab, Charleston, SC 29412 USA
[7] Zhengzhou Univ, Affiliated Hosp 1, Sch Med, Zhengzhou 450052, Henan, Peoples R China
关键词
GROWTH-FACTOR-BETA; HEPATOCELLULAR-CARCINOMA; TUMOR-GROWTH; MOUSE MODEL; ACTIVATION; EXPRESSION; CHAPERONE; THERAPY; METASTASIS; MECHANISMS;
D O I
10.1126/sciimmunol.aai7911
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页数:12
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