肾癌细胞PAK1活化促进肿瘤相关中性粒细胞分泌Galectin-9调控免疫细胞亚群诱导免疫逃逸的机制研究

Immune escape plays an important role in renal tumor cells development, invasion and metastasis under immune surveillance. Aberrant chemokines secreted by tumor cell, which have been observed in most human malignancies, can modulate the functional phenotype of immune cells that extensively reside in tumor microenvironment. These immune cells “functional phenotype switch” promote tumor progression as a case of immune surveillance dysfunction and immune escape. Our previous works have proved that the high expression of serine/threonine-protein kinases p21-activated kinase 1 (PAK1) has a key role in tumor development, drug resistance through different pathway. In this research, we found that increased PAK1 expression levels in surgically resected renal cell carcinoma (RCC) tumor tissues are higher than paired peritumor tissues, the intratumoral PAK1 expressions correlated significantly with clinical TNM stages, targeted therapy survivals, local neutrophils infiltration and their tumor-associated molecular phenotype. Furthermore, the secretions of chemokine IL-8 conferred by high-PAK1 RCC cells may mediate tumorigenic phenotype transformation of tumor-associated neutrophils (TANs). Based on these preliminary data, our current project proposal is designed to further elucidate the regulatory effect and functional significance of PAK1-mediated IL-8 secretion in RCC tumor progressions, especially its regulatory effect on TANs phenotype activated through CXCR1, mainly focus on the molecular mechanism and functional significance of the tumor cells--T cells cross-talk through Galectin-9 expression of TANs. The intrinsic model of molecular regulation pathway established by this research may help to develop PAK1 signaling based biomarker to improve preclinical diagnose sensitivity, postsurgical administration decision or survival prediction, and pave the way to the clinical investigation and drug discovery based on PAK1-mediated immune changes targeted therapy in current clinical managements of high-risk RCC patients.

肾癌细胞与肿瘤浸润免疫细胞相互作用形成免疫抑制微环境以逃避机体免疫监视在肾癌发生发展、复发转移和治疗抵抗过程中发挥重要作用。项目申请人前期研究发现，肾癌患者肿瘤组织中丝/苏氨酸激酶PAK1信号活化通过促进肿瘤细胞干细胞样表型参与肾癌发生发展与治疗抵抗（Cell Death Dis 2015， Int J Urol 2015），进一步分析发现肾癌组织PAK1信号活化与肿瘤浸润杀伤性T细胞功能抑制显著相关，肾癌细胞通过分泌IL-8招募活化肿瘤相关中性粒细胞表达抑制性免疫分子Galectin-9在其中发挥关键作用。本申请项目拟在前期发现的基础上，阐述肾癌细胞促癌信号PAK1活化调控肿瘤相关中性粒细胞功能表型转化介导免疫逃逸的细胞和分子机制，建立肿瘤相关中性粒细胞功能表型变化参与肾癌细胞促癌信号PAK1活化诱导免疫逃逸的分子调控和靶向干预模型，为认识肾癌发生机制、探索新的肿瘤治疗靶点奠定理论基础。

在本国家自然科学基金面上项目资助下，项目申请人围绕泌尿系统肿瘤（肾癌、膀胱癌）“治疗反应性预测和治疗新靶点发现”两大关键科学问题，深入探寻肾癌和膀胱癌分子变异-免疫微环境互作网络影响患者治疗反应性的功能及细胞分子机制，并取得一系列研究成果，以通讯作者和第一作者（含共同）在Journal for ImmunoTherapy of Cancer（2020a、2020b）、European Journal of Cancer（2022）、British Journal of Cancer（2022a、2022b、2022c）、International Journal of Cancer（2020）等肿瘤学领域国际权威期刊发表SCI论文10篇（包含10分以上3篇）。研究发现，PAK1促癌信号活化在肿瘤的发生发展过程中发挥了重要作用。基于以包括PAK1信号活化在内的肿瘤分子事件和中性粒细胞极化在内的微环境免疫特征，申请人主要取得了以下两项学术成绩：1. 建立基于肿瘤细胞分子变异和浸润免疫细胞亚群分化的治疗反应性预测模型；2. 发现特殊免疫细胞亚群作为免疫治疗新靶点。本项目具体阐明了中性粒细胞、CD8+T细胞、肿瘤相关巨噬细胞等肿瘤浸润免疫细胞亚群分化在肿瘤特定分子事件诱导免疫逃逸形成过程中的关键作用和分子机制，这些发现有助于促进临床上特定分型患者个体化治疗方案的制定和肿瘤免疫治疗新靶点的发现。