Thrombocytes in Cancer Immunity

 描述（由申请方提供）：血小板或血小板主要用于止血。越来越多地，它们通过TGFβ、VEGF、MMP-2、ATP和其他介质参与癌症进展和转移。此外，血小板可以通过GPIb、P-选择素和TREM-I配体激活中性粒细胞来调节先天免疫和炎症。它们还显示通过CD 40 L-CD 40途径激活树突状细胞（DC），并通过将细菌抗原穿梭至DC来促进抗原交叉呈递。然而，令人惊讶的是，血小板在抗肿瘤免疫中的作用在该领域很少受到关注，并且仍然不确定，尽管抗血小板剂在许多大型临床研究中似乎有效地预防癌症进展。特别是，癌症相关的血小板增多症与不良的临床结果相关，但其潜在机制尚不清楚。一个具体而重要的问题是有关血小板在形成癌症相关的免疫力，通过活化血小板（SAP）的分泌组中的大量分子的作用。我们的初步研究表明，SAP通过稳定和可分级的可溶性因子抑制CD 4和CD 8 T细胞的活化和效应功能。此外，使用我们独特的小鼠血小板减少症模型，由于损失的gp 96，一个强制性的伴侣的血小板GPIb-IX-V复合物，我们表明，血小板显着促进甲基胆蒽（MCA）诱导的纤维肉瘤。肿瘤的发展与循环髓源性抑制细胞（MDSC）的减少，更丰富的肿瘤浸润性CD 8 T细胞和T细胞效应功能的增加显着相关。最后，使用过继性T细胞转移策略，我们发现血小板减少症促进体内CD 8 T细胞的抗黑色素瘤免疫，这与MDSC的减少相关。我们的研究使我们假设血小板通过促进MDSC和抑制T细胞活化和功能在癌症免疫监视中发挥负性和免疫调节作用。这一新的假设将通过四个具体目标来解决。目的1将通过回答在PF 4-gp 96 KO小鼠中MCA诱导的纤维肉瘤的减少是否是由于增强的适应性免疫而确定血小板是否参与癌症免疫监视。我们还将确定血小板缺陷是否增强了针对多种肿瘤系统的肿瘤特异性免疫的启动。目的2将使用我们有前途的生化策略来确定血小板分泌组钝化CD 4和CD 8 T细胞活化的分子机制。目的3将揭示在用肿瘤特异性CD 8 T细胞过继治疗肿瘤的背景下血小板-MDSC串扰的机制。我们的最终目标将使我们能够优化血小板靶向策略，以增强黑色素瘤的免疫治疗。总的来说，我们的研究将揭示血小板促进癌症的潜在免疫机制，并将巩固免疫疗法和抗血小板药物组合作为对抗癌症的新型有效策略的想法。

 DESCRIPTION (provided by applicant): Thrombocytes or platelets function primarily in hemostasis. Increasingly, they have been implicated in cancer progression and metastasis via TGFβ, 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.