ITGB8+血小板通过募集激活CAFs影响肿瘤免疫检查点抑制剂疗效的机制研究

免疫检查点抑制剂已成为多种晚期恶性肿瘤的有效治疗手段，进一步通过改造免疫微环境提高其疗效是目前的研究热点。血小板参与了恶性肿瘤的多个进程，然而其对肿瘤免疫微环境的影响鲜有报道。前期研究通过数据库分析发现血小板浸润可导致“冷肿瘤”的微环境表型，表现为CAFs浸润增加，TILs减少。进一步通过体外实验及血小板升高、减少的小鼠模型发现ITGB8+血小板在募集激活CAFs的过程中发挥了重要作用，预实验结果表明ITGB8+血小板、CAFs及肿瘤细胞三者之间可能存在着正反馈的环路，而其中ITGB8+外泌体作为信号传递载体参与了上述过程。本项目将继续深入研究“ITGB8+血小板-CAFs-肿瘤细胞”正反馈环路促进“冷肿瘤”免疫表型形成的机制，明确这些相互作用对免疫检查点抑制剂疗效的影响，并探讨靶向ITGB8提高免疫检查点抑制剂疗效的可行性，为有效的免疫检查点抑制剂治疗联合方案提供实验依据。

Immune checkpoint inhibitors (ICIs) have shown their efficacy in treating multiple advanced tumors. Modifying of the immune microenvironment to improve the anti-tumor efficacy of the ICIs is a much focused research area. The platelets are involved in multiple processes of malignant tumors, but their impact on tumor immune microenvironment has seldom been reported. Our preliminary study found via database analysis that platelet infiltration lead to a "cold tumor" microenvironment phenotype, shown as increased CAFs infiltration and decreased TILs. Further in vitro experiments and mouse models of platelet elevation and reduction showed that ITGB8+ platelets played an important role in the recruitment and activation of CAFs. The preliminary study indicated the possible existence of a positive feedback loop among the ITGB8+ platelets, CAFs and tumor cells, while the ITGB8+ exosomes participated in the above-mentioned process as a signal carrier. In the present study, we would further study the positive feedback loop of “the ITGB8+ platelets - CAFs - tumor cells” in promoting the formation of the “cold tumor” immune phenotype for the purpose of clarifying the impact of these interactions on the efficacy of ICIs, and to discuss the rationale of targeting ITGB8 to improve the efficacy of the ICIs, so as to provide the experimental basis for an effective ICI-based combination regimen.