肿瘤微环境补体C5a/C5aR信号以多种方式促肿瘤进展，如其促巨噬细胞M2型极化诱导肺癌免疫耐受。我们曾发现肺癌细胞过表达C5aR1促肿瘤进展；近期用二代测序与蛋白组学检测C5a处理高表达C5aR1的肺癌细胞，发现处理后免疫检查点GAL-9明显上调而PD-L1、IL10等无变化。GAL-9作用其配体TIM-3可抑制固有与适应性免疫细胞，结合GAL-9/TIM-3被证实为抗PD-1治疗获得性耐药的机制，我们推测C5a/C5aR1信号活化通过GAL-9/TIM-3诱导肺癌免疫耐受。故拟于组织中分析C5a/C5aR1、GAL-9与PD-L1等表达及与肿瘤浸润CD8/CD4+T细胞等两两间的相关性及预后意义；细胞中研究C5a对GAL-9表达调节及机制并证实C5a/C5aR1-GAL-9-免疫耐受轴促肺癌进展；动物中验证此轴及评价其作为肺癌免疫治疗靶点的价值；从而揭示肺癌免疫耐受新机制及治疗新靶点。

Complement C5a/C5aR in tumor microenvironment promotes tumor progression via a variety of ways. For instance, its activation promotes self M2-polarization to induce the immune tolerance of lung cancer in macrophages. We have previously found that high level of C5aR1 in cancer cells promotes lung cancer progression. Recently, we employed RNA-sequencing and proteomics to determine the different mRNAs and proteins in lung cancer cells with discrepant expression of C5aR1 under C5a treatment, and found that immune checkpoint molecules GAL-9 was up-regulated significantly rather than the PD-L1, etc. The combination of GAL-9 and its ligand TIM-3 inhibits innate and adaptive immune cells. Moreover, the activation of GAL-9/TIM-3 has been proved to be a mechanism of acquired resistance to anti-PD-1 treatment. Thus, we speculate that C5a/C5aR1 signaling in cancer cells induces lung cancer immune tolerance through GAL-9/TIM-3. Therefore, we intend to analyze the correlation between the expression of C5a/C5aR1, GAL-9, PD-L1 and tumor infiltration CD8/CD4+T cells in lung cancer tissues; then investigate the specific regulation and mechanism of C5a on the expression of GAL-9 in cells overexpressing C5aR, and reveal the involvement of C5a/C5aR1-GAL-9/immune tolerance axis in lung cancer progression; finally, we try to verify C5a/C5aR1-GAL-9/immune tolerance axis in lung cancer progression in vivo experiments and explore the potential value as a target for lung cancer immunotherapy, so as to disclose a new mechanism in immune tolerance and provide new targets for immunotherapy in lung cancer.