GPR35的活化促进肺腺癌细胞增殖和ILC2s诱导的免疫逃逸在培美曲塞耐药中的作用及机制研究

The imbalance of apoptosis and proliferation is the pivotal factor of Pemetrexed resistance of lung adenocarcinoma (LUAD), in which process immuno-escape plays vital role. Our prophase results showed Pemetrexed resistance and immuno-escape induced by G coupled protein receptor 35 (GPR35) and Group 2 innate lymphoid cells (ILC2s), respectively, leading to cell proliferation of LUAD. Lysophosphatidic acid (LPA), the ligand of GPR35, was accordingly up-regulated in culture medium of LUAD cells after Pemetrexed treatment. Consequently, our project is focusing on: the role of GPR35 in regulating LUAD cells proliferation and immune escape in Pemetrexed resistance. In this project, we plan to explore the role of GPR35 in mediating the imbalance of proliferation and apoptosis in LUAD cells and promoting ILC2s induced immune escape, respectively, elucidate the molecular mechanism of GPR35 in promoting Pemetrexed resistance and provide novel strategy to predict and reverse Pemetrexed resistance of LUAD.

肺腺癌培美曲塞耐药的关键是肿瘤细胞增殖与凋亡的失衡，免疫调节异常导致的肿瘤逃逸亦与肿瘤耐药密切相关。本项目预初实验发现，G蛋白偶联受体35（GPR35）活化可导致肺腺癌细胞抵抗培美曲塞并进一步增殖和Ⅱ型固有淋巴细胞（ILC2s）诱导的肿瘤免疫逃逸；肺腺癌细胞在培美曲塞压力下凋亡并释放溶血磷脂酸（LPA）。已知LPA是GPR35的配体。鉴此，我们聚焦的科学问题是：GPR35调控的肺腺癌细胞增殖和免疫逃逸在培美曲塞耐药中的作用。本项目拟以GPR35调控为切入点，系统研究和揭示GPR35介导肺腺癌细胞增殖与凋亡失衡和介导ILC2s诱导免疫逃逸的作用，及其促进培美曲塞耐药的分子机制；明晰干预LPA-GPR35调控轴逆转肺腺癌培美曲塞耐药的作用。籍此，为临床形成预测并遏制肺腺癌培美曲塞耐药的新策略奠定理论基础和提供实验依据。

肿瘤耐药的关键是肿瘤细胞增殖与凋亡的失衡，免疫调节异常导致的肿瘤逃逸亦与肿瘤耐药密切相关。本项目在原计划的基础上，首先证实了IL-33其可通过逆转ILC2的抑制性，放大免疫应答反应，而IL-33联合PD-1治疗，ILC2的功能进一步被放大，一方面IL-33富集ILC2，另一方面还可逆转ILC2的抑制性；分选ILC2，与肿瘤细胞共培养，其KLRG1的表达被抑制，这一现象在运用Anti-PD-1封闭之后被逆转。ILC2和T细胞共存于肿瘤微环境中，并具有相同的刺激途径和抑制途径，同时，本项目同时发现，干预GPR35可有效调控ILC2/NK的免疫平衡，参与抗肿瘤免疫应答，基于以上，本项目提供了可同时调控固有免疫和适应性免疫应答的新的干预靶点，因此，共同靶向抗癌ILC2和T细胞的免疫治疗策略可能具有广泛的应用价值。