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。

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.