Zhao Peiyan, Sun Xiaodan, Li Hui, Liu Yan, Cui Yanan, Tian Lin, Cheng Ying
Postdoctoral Research Workstation, Jilin Cancer Hospital, Changchun 130012, China.
Medical Oncology Translational Research Lab, Jilin Cancer Hospital, Changchun 130012, China.
Cancers (Basel). 2022 Jan 18;14(3):457. doi: 10.3390/cancers14030457.
SCLC is an aggressive malignancy with a very poor prognosis and limited effective therapeutic options. Despite the high tumor mutational burden, responses to immunotherapy are rare in SCLC patients, which may be due to the lack of immune surveillance. Here, we aimed to examine the role and mechanism of oncogene in the regulation of NKG2DL, the most relevant NK-activating ligand in SCLC-N. Western Blotting, Immunofluorescence, flow cytometry, quantitative real-time PCR (qRT-PCR), Co-Immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and Cytotoxicity assay were used on H2227 cells, H446 cells, and other SCLC cell lines, and we found that c-Myc negatively regulated NKG2DL expression in SCLC-N cells. Mechanistically, c-Myc recruited HDAC3 to deacetylate H3K9ac at the promoter regions of and , suppressing the MICA/B expression of SCLC-N cells and the cytotoxicity of NK cells. Treatment with selective HDAC3 inhibitor up-regulated the expression of NKG2DL on SCLC-N cells and increased the cytotoxicity of NK cells. Furthermore, analysis of the CCLE and Kaplan-Meier plotter data performed the negative correlation between and in SCLC-N cells and the correlation with the prognosis of lung cancer patients. Collectively, the results provided the new insight into the role and mechanism of c-Myc/HDAC3 axis in NKG2DL expression and innate immune escape of SCLC-N, suggesting the potential target for SCLC-N immunotherapy.
小细胞肺癌（SCLC）是一种侵袭性恶性肿瘤，预后很差，有效治疗选择有限。尽管肿瘤突变负荷高，但SCLC患者对免疫疗法的反应很少，这可能是由于缺乏免疫监视。在这里，我们旨在研究癌基因在调节NKG2DL（SCLC-N中最相关的自然杀伤细胞（NK）激活配体）中的作用和机制。我们对H2227细胞、H446细胞和其他SCLC细胞系进行了蛋白质免疫印迹法、免疫荧光法、流式细胞术、定量实时聚合酶链反应（qRT-PCR）、免疫共沉淀（Co-IP）、染色质免疫沉淀（ChIP）和细胞毒性测定，发现c-Myc负向调节SCLC-N细胞中NKG2DL的表达。机制上，c-Myc招募组蛋白去乙酰化酶3（HDAC3）使MICA和MICB启动子区域的组蛋白H3赖氨酸9乙酰化（H3K9ac）去乙酰化，抑制SCLC-N细胞的MICA/B表达和NK细胞的细胞毒性。用选择性HDAC3抑制剂处理可上调SCLC-N细胞上NKG2DL的表达，并增加NK细胞的细胞毒性。此外，对癌症细胞系百科全书（CCLE）和Kaplan-Meier绘图仪数据的分析显示，SCLC-N细胞中MICA和MICB之间呈负相关，且与肺癌患者的预后相关。总的来说，这些结果为c-Myc/HDAC3轴在SCLC-N的NKG2DL表达和先天免疫逃逸中的作用和机制提供了新的见解，提示其可能成为SCLC-N免疫治疗的靶点。
