Lv Jiadi, Zhou Yabo, Zhou Nannan, Wang Zhenfeng, Chen Jie, Chen Haoran, Wang Dianheng, Zhou Li, Wei Keke, Zhang Huafeng, Tang Ke, Ma Jingwei, Liu Yuying, Wan Yonghong, Zhang Yi, Zhang Haizeng, Huang Bo
Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing 100005, China.
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Sci Transl Med. 2023 Feb;15(681):eabq6024. doi: 10.1126/scitranslmed.abq6024. Epub 2023 Feb 1.
Weak immunogenicity of tumor cells is a root cause for the ultimate failure of immunosurveillance and immunotherapy. Although tumor evolution can be shaped by immunoediting toward a less immunogenic phenotype, mechanisms governing the initial immunogenicity of primordial tumor cells or original cancer stem cells remain obscure. Here, using a single tumor-repopulating cell (TRC) to form tumors in immunodeficient or immunocompetent mice, we demonstrated that immunogenic heterogeneity is an inherent trait of tumorigenic cells defined by the activation status of signal transducer and activator of transcription 1 (STAT1) protein in the absence of immune pressure. Subsequent investigation identified that the RNA binding protein cold shock domain-containing protein E1 (CSDE1) can promote STAT1 dephosphorylation by stabilizing T cell protein tyrosine phosphatase (TCPTP). A methyltransferase SET and MYN domain-containing 3 (SMYD3) was further identified to mediate H3K4 trimethylation of locus, which was under the regulation of mechanotransduction by cell-matrix and cell-cell contacts. Thus, owing to the differential epigenetic modification and subsequent differential expression of CSDE1, nascent tumorigenic cells may exhibit either a high or low immunogenicity. This identified SMYD3-CSDE1 pathway represents a potential prognostic marker for cancer immunotherapy effectiveness that requires further investigation.
肿瘤细胞的弱免疫原性是免疫监视和免疫治疗最终失败的根本原因。尽管肿瘤进化可通过免疫编辑形成免疫原性较低的表型，但原始肿瘤细胞或原始癌症干细胞初始免疫原性的调控机制仍不清楚。在此，我们利用单个肿瘤再增殖细胞（TRC）在免疫缺陷或免疫健全小鼠中形成肿瘤，证明了免疫原性异质性是肿瘤发生细胞的固有特性，其由信号转导和转录激活因子1（STAT1）蛋白在无免疫压力情况下的激活状态所定义。后续研究发现，RNA结合蛋白冷休克结构域包含蛋白E1（CSDE1）可通过稳定T细胞蛋白酪氨酸磷酸酶（TCPTP）促进STAT1去磷酸化。进一步鉴定出一种甲基转移酶SET和含MYN结构域蛋白3（SMYD3）介导该位点的H3K4三甲基化，其受细胞-基质和细胞-细胞接触的机械转导调控。因此，由于CSDE1的表观遗传修饰差异及随后的差异表达，新生肿瘤发生细胞可能表现出高或低免疫原性。这一鉴定出的SMYD3-CSDE1通路代表了癌症免疫治疗有效性的潜在预后标志物，有待进一步研究。
