基于c-Myc对NKG2DLs表达调控的SCLC抗肿瘤免疫治疗的机制研究

SCLC免疫治疗取得重大突破，但获益人群有限，可能与杀伤性免疫细胞浸润较少有关。研究和申请者前期证明，肿瘤NKG2DL不仅激活杀伤性免疫细胞，还募集其至肿瘤巢内。但大多数SCLC低表达NKG2DL，c-Myc与NKG2DL表达、浸润免疫细胞数量呈反比。申请者证明NKG2DL启动子含c-Myc抑制基因的富集序列且mRNA 3’UTR含c-Myc激活的miR-17-92结合区，且研究报道c-Myc参与抑制其他肿瘤免疫治疗效果，推测c-Myc调控NKG2DL表达影响SCLC免疫细胞浸润及免疫治疗效果。鉴于此，通过调控c-Myc表达和miRNA转录、检测NKG2DL启动子结合、c-Myci联合免疫治疗模型小鼠、评估患者免疫治疗反应等，研究c-Myc对SCLC NKG2DL调控作用及机制和免疫治疗作用影响。期望为c-Myc成为通过上调肿瘤NKG2DL表达促进SCLC免疫治疗效果的新靶点提供实验基础。

Although the immunotherapy of SCLC has made new progression, the number of patients who benefited is limited, which may be related to the less infiltration of cytotoxic immune cells. The research and the applicant's previous work showed that NKG2DL on the surface of tumor not only activates cytotoxic immune cells, but also recruits the cytotoxic immune cells to the tumor nest. However, most SCLCs express low level of NKG2DL, and the expression level of c-Myc is in inverse proportion to the expression level of NKG2DL and the number of infiltrating immune cells. The applicant has proved that the promoter of NKG2DL contains the enriched sequence of c-Myc suppressed gene and the 3'UTR of NKG2DL mRNA contains the c-Myc-activated miR-17-92 binding region. Together with the reports that c-Myc is involved in suppressing the effect of immunotherapy, we speculate that the regulation of c-Myc on the NKG2DL expression affects the effect of SCLC immunotherapy. Based on the findings, we plan to study the effect and mechanism of c-Myc on NKG2DL expression and immunotherapy of SCLC by regulating c-Myc expression and miR-17-92 transcription, detecting NKG2DL promoter binding and therapeutic efficacy of c-Myci combined immunotherapy, and evaluating the response of patients to immunotherapy. This work may provide the experimental basis for c-Myc to become a new target that promotes SCLC immunotherapy by up-regulating the expression of NKG2DL on tumor cells.