胃癌细胞Notch1信号活化诱导肿瘤免疫逃逸机制研究

Immunotherapy emerged as a promising strategy for patients with advanced gastric cancer, but limited patients respond effectively to the treatment. The phenotype transformation of tumor infiltrating immune cells that lead to immune escape was the main reason for immunotherapy treatment failure. Our preliminary research found that Notch1 signaling activation could promote tumor progression by conferring stem-cell like phenotype to gastric cancer cell (Br J Cancer 2014). Besides, the dysfunctional state of tumor infiltrating immune cell, including intratumoral IL17-producing cells, tumor infiltrating neutrophils, tumor associated macrophages and tumor infiltrating mast cells, contributing to an immunosuppressive microenvironment that could lead to immune escape, played critical roles in tumor progression (Ann Oncol 2019; Ann Surg 2018; Gastric Cancer 2015; Brit J Surg 2017). Our previous study found that Notch1 signaling activation in gastric cancer cells could promote CCL2 secretion and tumor associated macrophages (TAMs) infiltration in tumor microenvironment, and correlated with the immunosuppressive phenotype. From the point view of tumor oncogenic signaling activation could promote immune escape, our present research will focused on exploring the molecular mechanism and functional significance of Notch1 activation mediated immune escape by clarifying Notch1 activation could promote CCL2 secretion that will chemo-attract TAMs infiltration and induce PD-L1 expression in TAMs to facilitate immune escape. Based on corresponding results, we will establish a molecular regulation and intervention model based on interrupting the interlinks between tumor cell intrinsic oncogenic signal activation and tumor microenvironment, which will pave the way to precise molecular stratification and drug discovery based on Notch1 activation mediated immune escape, facilitate individualized targeted therapy development and promote immunotherapy effect for gastric cancer.

免疫疗法为晚期胃癌患者治疗带来曙光，但只有部分患者对治疗产生有效应答，肿瘤浸润免疫细胞功能表型转化所致免疫逃逸是免疫治疗无应答的重要原因。项目申请人前期研究发现，胃癌细胞Notch1活化通过促进胃癌干细胞样表型参与肿瘤发生发展 (Br J Cancer 2014)，肿瘤浸润免疫细胞功能表型转化介导的免疫逃逸在其中发挥关键作用(Ann Oncol 2019; Ann Surg 2018; Gastric Cancer 2015; Br J Surg 2017)。进一步研究发现胃癌细胞Notch1活化招募并促进肿瘤相关巨噬细胞（TAMs）表型转化介导免疫逃逸。本申请项目拟在前期基础上，阐明胃癌细胞Notch1信号活化招募并激活TAMs介导免疫逃逸的细胞和分子机制，建立胃癌细胞Notch1活化诱导免疫逃逸的分子调控和靶向干预模型，为开发个体化靶向治疗治疗药物、提高免疫治疗效果奠定基础。

肿瘤细胞中促癌信号的激活是肿瘤发生的始动因素。促癌信号的活化在赋予肿瘤细胞恶性潜能的同时，也会影响肿瘤微环境，尤其是影响抑制性免疫细胞的浸润激活、杀伤性免疫细胞的失活、抑制性细胞因子的产生等进而诱导微环境免疫抑制状态，促进肿瘤免疫逃逸。在青年科学基金项目的资助下，项目负责人对上述胃癌细胞促癌信号活化诱导肿瘤相关巨噬细胞浸润等肿瘤浸润免疫细胞重编程促进胃癌免疫逃逸的功能及其分子机制进行了深入研究，发现ARID1A野生型胃癌招募并活化免疫抑制性TAMs亚群，促进CD4+Th细胞向抑制性CD4+Trm及RORγt+FOXP3+表型偏转，同时下调IL-9等免疫激活性分子，抑制患者免疫治疗疗效（Oncoimmunology, 2020a; Oncoimmunology, 2020b; Cancer Immunol Immunother, 2021a; Cancer Immunol Immunother, 2022）；发现胃癌细胞通过CD47-SIRPα信号轴诱导TAMs向“M2”方向极化，分泌IL-10并诱导下游CD8+T细胞功能耗竭，促使胃癌免疫逃逸（Oncoimmunology, 2021; Cancer Immunol Immunother, 2021b; Annals of Surgery, 2022）；发现弥漫性胃癌中“M2”型巨噬细胞显著富集，其上调TGF-β、IDO1等免疫抑制因子，促进CD8+T细胞LAG-3、PDPN等免疫检查点上调，形成促肿瘤免疫微环境，降低患者免疫治疗获益（Cancer Immunol Immunother, 2020; Oncoimmunology, 2020c; Int J Cancer, 2021）。这些发现有利于更加深入、全面地了解肿瘤微环境及肿瘤细胞协同作用导致疾病发生进展的重要功能机制，并为探索靶向上述协同过程中的关键组分及其与现有治疗策略联用策略提供新的理论基础。