CD155在肿瘤细胞与单核/巨噬细胞协同促进卵巢癌免疫逃逸中的作用与机制研究

PD-L1/PD-1免疫治疗在多种肿瘤中已取得极大成功，但在卵巢癌中客观缓解率较低，进一步挖掘卵巢癌免疫逃逸机制，有助于卵巢癌免疫疗法的突破。CD155-TIGIT/CD226轴是近年发现的新免疫卡控点通路。我们前期发现，①卵巢癌组织中CD155表达显著高于PD-L1，且肿瘤中浸润的单核/巨噬细胞也高表达CD155的新现象；②CD155高表达的肿瘤细胞及单核细胞均能显著下调CD8+ T细胞活化性受体CD226表达；③肿瘤细胞可诱导单核细胞CD155表达增加，二者还可协同抑制T细胞CD226并提高TOX表达；④TIGIT单抗可降低二者对T细胞的抑制作用。前期研究提示卵巢癌免疫逃逸与CD155密切相关，且存在免疫微环境中单核/巨噬细胞协同机制。本项目拟从临床标本、体外细胞、动物模型三个层面入手，系统阐明CD155在卵巢癌免疫逃逸中的功能及作用机制。本项目的完成将有望为卵巢癌免疫治疗提供新思路。

The response rate of PD-L1/PD-1 blockade immunotherapy in ovarian cancer is lower than that of other malignancies, thus, there is an urgent need to investigate the dominant pathway regulating immune escape of ovarian cancer, which will likely contribute to more promising targeted immunotherapies against ovarian cancer. CD155-TIGIT/CD226 axis is a novel immune checkpoint pathway. In the preliminary study, we observed that (i) the expression of CD155 in tumor tissue was higher than PD-L1, intriguingly, CD155 was not only expressed at high levels on tumor cells, but also on tumor-infiltrating monocytes/macrophages; (ii) besides CD155high tumor cells, CD155high monocytes were equally capable of downregulating the expression of costimulatory receptor CD226 on CD8+ T cells; (iii) tumor cells could induce CD155 expression on monocytes, moreover, the synergy between tumor cells and monocytes could further diminish CD226 expression, on the contrary, enhance the expression of TOX; (iiii) importantly, TIGIT blockade partially abrogated the synergistic suppressive effects of tumor cells and monocytes on T cell activation. Taken together, the above findings suggest that CD155-TIGIT/CD226 axis is closely associated with immune escape of ovarian cancer, and the synergy between tumor cells and monocytes/macrophages foster an immunosuppressive tumor microenvironment. This project intends to systematically clarify the effects of CD155 in immune escape of ovarian cancer and its underlying mechanisms utilizing clinical specimens, ex vivo cells, mouse ovarian tumor and Patient-Derived tumor Xenograft (PDX) models. It is expected to provide a novel avenue for ovarian cancer immunotherapy.