阻断VEGF/VEGFR-2信号通路逆转TAMs极化在乳腺癌T细胞免疫中的作用及机制研究

Tumor-associated macrophages (TAMs) are the major immune cells in infiltrating breast cancer microenvironment. TAMs polarizing to type M2 and thus inhibiting T cell immune activation are one of the key factors which leads to tumor immune escape. However, the regulation of TAMs polarization and their influence on T cells are not clear yet. Our previous study showed that T cells in breast cancer cell nest decreased significantly. The proportion of type M2 TAMs increased in breast cancer tissue and after induction with breast cancer culture medium. Accordingly, the expression levels of VEGF, VEGFR-2 and PDL-1 proteins also increased. When M2-TAMs are polarized towards type M1 by blocking VEGF/VEGFR-2 signaling in vitro, Th1 cytokines secretion increased, Th2 cytokines secretion decreased, and the expression level of PD-L1 membrane protein decreased. Based on our own results and previous works, we propose that targeted blocking of VEGF/VEGFR-2 signaling promotes the polarization of TAMs from M2 to M1, reverses TAMs-mediated immunosuppressive environment, promotes T cell immune activation, and suppresses breast cancer progression. The mechanisms underlying reversing M2-TAMs polarization and promoting T cell immune activation by blocking of VEGF/VEGFR-2 signaling will be investigated both in vivo and in vitro. The results will give new insights into and new strategies for the immunotherapy of breast cancer.

肿瘤相关巨噬细胞（TAMs）是浸润乳腺癌组织主要的免疫细胞，TAMs向M2型极化是导致肿瘤免疫逃逸的重要因素，但TAMs极化机制及其对T细胞的作用仍不清楚。前期实验发现：浸润乳腺癌癌巢的T细胞明显减少，乳腺癌微环境作用下M2型TAMs比例增高，VEGF、VEGFR-2及PD-L1蛋白表达增高；体外阻断VEGF/VEGFR-2信号传导促进M2型TAMs向M1极化，且Th1型细胞因子分泌增多，Th2型细胞因子分泌减少及膜PD-L1表达降低。基于前期研究结果和文献报道，课题组提出假设：靶向阻断VEGF/VEGFR-2信号通路促进M2型TAMs向M1极化，逆转TAMs介导的免疫抑制环境，增强T细胞免疫活化，从而抑制乳腺癌进展。课题组将从体内外深入研究阻断VEGF/VEGFR-2信号通路逆转TAMs极化增强乳腺癌T细胞免疫活化及机制，为乳腺癌免疫治疗提供新策略。

肿瘤相关巨噬细胞（TAMs）是浸润乳腺癌组织主要的免疫细胞，TAMs向M2型极化是导致肿瘤免疫逃逸的重要因素，但TAMs极化机制及其对T细胞的作用仍不清楚。前期实验发现：浸润乳腺癌癌巢的T细胞明显减少，乳腺癌微环境作用下M2型TAMs比例增高，VEGF、VEGFR-2及PD-L1蛋白表达增高；体外阻断VEGF/VEGFR-2信号传导促进M2型TAMs向M1极化，且Th1型细胞因子分泌增多，Th2型细胞因子分泌减少及膜PD-L1表达降低,在Bevacizumab及Apatinib的治疗下，裸鼠生长瘤体速度受到抑制。瘤体组织中Ki67及VEGF及VEGFR-2阳性率下降。抗炎因子IL-10及ARG-1表达水平上升巨噬细胞的VEGF/VEGFR-2信号通路被阻断后，M1/M2比例上升，T细胞分泌的促炎因子TGF-β、IL-6及 IL-12水平下降。与巨噬细胞共培养的4T1细胞增殖能力、迁移侵袭能力及克隆能力下降，阻断VEGF/VEGFR-2信号通路能促进TAMs向M1极化，可以抑制乳腺癌细胞转移迁移侵袭。本课题从体内外深入研究阻断VEGF/VEGF R-2信号通路逆转TAMs极化增强乳腺癌T细胞免疫活化及机制，为乳腺癌免疫治疗提供新策略。

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