EGFR-TKI诱导肿瘤非依赖的MDSC上调和对宿主免疫的抑制作用及机制研究

免疫治疗给肺癌患者带来巨大获益，但EGFR突变的肺腺癌患者获益有限，亟需寻求有效治疗策略。这些患者通常在EGFR-TKI治疗后才会接受免疫治疗。我们前期发现，未荷瘤小鼠和肺癌根治术后患者在接受EGFR-TKI治疗后，血液MDSC显著上调，而小鼠还观察到脾脏和骨髓MDSC均升高，测序与生信分析提示其与肿瘤组织来源的MDSC表达谱高度相似，S100A8/A9等多免疫抑制相关分子上调。小鼠模型接种MC38肿瘤生长加快。我们因此推测，EGFR-TKI可通过诱导肿瘤非依赖的MDSC上调，抑制机体免疫和免疫治疗疗效。进一步研究发现，G-CSF、IL-1β和VEGF等多个与MDSC产生与激活相关细胞因子在血液中显著升高，支持该假设。本项目将在前期基础上研究EGFR-TKI诱导MDSC上调的作用、影响及其机制，在此基础上优化免疫治疗策略。本项目的顺利实施有望为EGFR突变肺腺癌患者的免疫治疗提供新思路。

Immunotherapy has brought substantial benefits to patients with lung cancer, but studies found that benefits were limited for patients with EGFR-mutant NSCLC, so it is urgent to develop an effective treatment strategy. These patients usually received EGFR-TKI treatment before immunotherapy. Our previous work found that EGFR-TKI treatment would induce a significant upregulation of MDSC in non-tumor-bearing mice and patients with lung cancer after radical resection. MDSCs in blood, spleen and bone marrow of the treated mice were significantly increased, while sequencing and bioinformatics analysis showed that they were highly similar to the expression profile of intratumoral infiltrated MDSC, with the up-regulation of S100A8/A9 and other immunosuppressive molecules; in MC38-inoculated mice tumor growing faster. We speculated that EGFR-TKI could inhibit the immune system by inducing the production of MDSCs, thereby impairing the efficacy of immunotherapy. Furthermore, we found that multiple cytokines such as G-CSF, IL-1βand VEGF that were associated with MDSC production and activation were significantly increased in the blood of mice, supporting this hypothesis. Our project will further study the inhibitory effect of EGFR-TKI-induced MDSC and its molecular mechanism based on the previous work, and continue to optimize the combined immunotherapy strategy. Patients with EGFR-mutated NSCLC accounting for a large proportion, our project is expected to provide new ideas for applying immunotherapy to these subgroup.