Thrombocytes in Cancer Immunity

癌症免疫中的血小板

基本信息

批准号：
10047658
负责人：
Zihai Li
金额：
$ 22.51万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10047658
关键词：
Address Adoptive Cell Transfers Antigens Antiplatelet Drugs Aspirin Attention Bacterial Antigens Biochemical Blood Platelets CD8-Positive T-Lymphocytes Clinical Clinical Research Combination immunotherapy Cross Presentation Data Defect Dendritic Cells Development Environment Gelatinase A Head and neck structure Hemorrhage Hemostatic function Immune Immune system Immunity Immunologic Monitoring Immunologic Surveillance Immunotherapeutic agent Immunotherapy Inflammation Knock-out Knockout Mice Ligands Link Malignant Neoplasms Mediator of activation protein Methylcholanthrene Molecular Molecular Chaperones Myeloid-derived suppressor cells Natural Immunity Neoplasm Metastasis Outcome P-Selectin Pathway interactions Patients Platelet Inhibitors Platelet Transfusion Play Reporting Role Shapes Suggestion System T cell therapy T-Cell Activation T-Lymphocyte TNFRSF5 gene TNFSF5 gene Thrombocytopenia Thrombospondins Transforming Growth Factor beta Treatment Protocols Tumor Immunity Vascular Endothelial Growth Factors adaptive immunity anti-cancer base cancer therapy clopidogrel effective therapy effector T cell fibrosarcoma immunoregulation in vivo melanoma mouse model neutrophil novel oligomycin sensitivity-conferring protein platelet function prevent public health relevance response thrombocytosis treatment strategy tumor tumor progression tumorigenesis

项目摘要

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.

描述（由申请人提供）：血小板或血小板的主要功能是止血，它们越来越多地通过 TGFβ、VEGF、MMP-2、ATP 和其他介质参与癌症进展和转移。通过 GPIb、p-选择素和 TREM-I 配体激活中性粒细胞，它们也被证明可以激活树突状细胞。 (DC)通过CD40L-CD40途径，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，尽管抗肿瘤免疫，但血小板在抗肿瘤免疫中的作用很少受到关注并且仍然不明确。 - 在许多大型临床研究中，血小板药物似乎可以有效预防癌症进展，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。我们的初步研究表明，SAP 通过可溶性因子抑制 CD4 和 CD8 T 细胞的激活和效应功能。此外，使用我们独特的由于 gp96（血小板 GPIb-IX-V 复合物的必需伴侣）丢失而导致的血小板减少症小鼠模型，我们发现血小板显着促进血小板减少。血小板减少环境中甲基胆蒽 (MCA) 诱导的纤维肉瘤的发展与循环骨髓源性抑制细胞 (MDSC) 的减少、肿瘤浸润性 CD8 T 细胞的增多以及 T 细胞效应功能的增加显着相关。通过过继性 T 细胞转移策略，我们发现血小板减少症可促进体内 CD8 T 细胞的抗黑色素瘤免疫，这与 MDSC 的减少相关。目标 1 将通过回答 PF4-gp96 KO 小鼠中 MCA 诱导的纤维肉瘤的减少是否是由于适应性免疫增强来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的肿瘤特异性免疫的启动。目标系统。 2 将使用我们有前途的生化策略来定义血小板分泌组减弱 CD4 和 CD8 T 细胞激活的分子机制。目标 3 将揭示在肿瘤特异性过继治疗的背景下血小板-MDSC 串扰的机制。 CD8 T 细胞。我们的最终目标是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，并将巩固这一想法。免疫疗法和抗血小板药物的结合是一种新颖有效的抗癌策略。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Endoplasmic reticulum heat shock protein gp96/grp94 is a pro-oncogenic chaperone, not a tumor suppressor.

内质网热休克蛋白 gp96/grp94 是一种促癌伴侣，而不是肿瘤抑制因子。

DOI：
发表时间：
2015-05
期刊：
影响因子：
0
作者：
Rachidi S;Sun S;Li Z
通讯作者：
Li Z

Membrane-organizing protein moesin controls Treg differentiation and antitumor immunity via TGF-β signaling.

膜组织蛋白 moesin 通过 TGF-β 信号控制 Treg 分化和抗肿瘤免疫。

DOI：
发表时间：
2017-04-03
期刊：
影响因子：
0
作者：
Ansa;Zhang, Yongliang;Yang, Yi;Hussey, George S;Howley, Breege V;Salem, Mohammad;Riesenberg, Brian;Sun, Shaoli;Rockey, Don C;Karvar, Serhan;Howe, Philip H;Liu, Bei;Li, Zihai
通讯作者：
Li, Zihai

Canopy Homolog 2 contributes to liver oncogenesis by promoting unfolded protein response-dependent destabilization of tumor protein P53.

Canopy Homolog 2 通过促进肿瘤蛋白 P53 的未折叠蛋白反应依赖性去稳定性来促进肝脏肿瘤发生。

DOI：
发表时间：
2022-12
期刊：
影响因子：
0
作者：
Hong, Feng;Lin, Ching Ying;Yan, Jingyue;Dong, Yizhou;Ouyang, Yuli;Kim, Doyeon;Zhang, Xiaoli;Liu, Bei;Sun, Shaoli;Gu, Wei;Li, Zihai
通讯作者：
Li, Zihai

CNPY2 is a key initiator of the PERK-CHOP pathway of the unfolded protein response.

CNPY2 是未折叠蛋白反应 PERK-CHOP 途径的关键启动子。

DOI：
发表时间：
2017-10
期刊：
影响因子：
16.8
作者：
Hong, Feng;Liu, Bei;Wu, Bill X;Morreall, Jordan;Roth, Brady;Davies, Christopher;Sun, Shaoli;Diehl, J Alan;Li, Zihai
通讯作者：
Li, Zihai

Surface Expression of TGFβ Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer.

TGFβ 对接受体 GARP 的表面表达促进乳腺癌的肿瘤发生和免疫耐受。

DOI：
10.1158/0008-5472.can-16-1456
发表时间：
2016-12-15
期刊：
Cancer research
影响因子：
11.2
作者：
Metelli A;Wu BX;Fugle CW;Rachidi S;Sun S;Zhang Y;Wu J;Tomlinson S;Howe PH;Yang Y;Garrett-Mayer E;Liu B;Li Z
通讯作者：
Li Z