Thrombocytes or platelets function primarily in hemostasis. Increasingly, they have been implicated in cancer progression and metastasis via TGF?, VEGF, MMP-2, ATP and other mediators. Moreover, platelets can regulate innate immunity and inflammation by activating neutrophils via GPIb, p-selectin and TREM-I ligand. They have also been shown to activate dendritic cells (DCs) via a CD40L-CD40 pathway, and promote antigen cross-presentation through shuttling bacterial antigens to DCs. Surprisingly, however, the roles of platelets in anti-tumor immunity have received little attention in the field and are still undefined, despite anti-platelet agents appearing to be effective in preventing cancer progression in a number of large clinical studies. In particular, cancer-associated thrombocytosis correlates with the poor clinical outcome, but the underlying mechanism is unclear. A specific and important question is related to the role of platelets in shaping cancer-associated immunity via a multitude of molecules in the secretome of activated platelets (SAP). Our preliminary studies have demonstrated that SAP suppresses activation and effector function of both CD4 and CD8 T cells by a soluble factor that is stable and fractionable. Moreover, using our unique mouse model of thrombocytopenia due to the loss of gp96, an obligatory chaperone for the platelet GPIb-IX-V complex, we show that platelets significantly promote methylcholanthrene (MCA)-induced fibrosarcoma. Tumor development in the thrombocytopenic environment correlated significantly with the reduction of circulating myeloid-derived suppressor cells (MDSCs), more abundant tumor-infiltrating CD8 T cells, and increased T cell effector function. Finally, using an adoptive T cell transfer strategy, we found that thrombocytopenia promoted anti-melanoma immunity by CD8 T cells in vivo that correlated with the reduction of MDSCs. Our studies led us to hypothesize that platelets play negative and immunoregulatory roles in cancer immunosurveillance via promoting MDSCs and suppressing T cell activation and functionality. This novel hypothesis will be addressed by the four specific aims.
Aim 1 will determine if platelets participate in cancer immune surveillance by answering if reduction of MCA-induced fibrosarcoma in PF4-gp96 KO mice is due to enhanced adaptive immunity. We will also determine if platelet defect enhances priming of tumor-specific immunity against multiple tumor systems.
Aim 2 will use our promising biochemical strategy to define the molecular mechanism by which the platelet secretome blunts CD4 and CD8 T cell activation.
Aim 3 will uncover the mechanism of platelet-MDSC cross-talk in the context of adoptive therapy of tumors with tumor-specific CD8 T cells.
Our final aim will allow us to optimize a platelet- targeted strategy to enhance immunotherapy of melanoma. Collectively, our study will uncover underlying immune-based mechanisms by which thrombocytes promote cancer and it will solidify the idea of a combination of immunotherapy and anti-platelet agents as a novel and effective strategy against cancer.

Public Health Relevance

Platelets function primarily in preventing and controlling bleeding, but they also have increasingly been reported to regulate the immune system. We have compelling evidence to support a novel concept that platelets dampen cancer immunity. Our proposal aims to understand the mechanism and implication of our new findings, which will very likely solidify the concept of employing a combination of immunotherapy and anti-platelet agents as a novel and effective treatment strategy for cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA188419-01A1
Application #
8883965
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
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