Jin Yuni, Lu Xiaoning, Liu Yuan, Su Liangdi, Bao Chan, Guo Huiming
Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, No. 295, Xichang Road, Wuhua District, Kunming, 650032 Yunnan People's Republic of China.
Cytotechnology. 2024 Aug;76(4):465-482. doi: 10.1007/s10616-024-00629-y. Epub 2024 Apr 24.
CD8 T cells are the primary mediators of anticancer immunity, and modulation of the CD8 T cell response has been a central focus of immunotherapy to treat cancer. When CD8 T cells specifically recognize antigenic peptides presented by the MHC-I on tumor cells, they become activated and kill the tumor cells. However, one pivotal mechanism through which tumor cells evade immune surveillance is to reduce their antigen presentation. To identify novel immunotherapeutic targets, we specifically focused on the role of MAL2 in immune evasion in endometrial cancer (EC) and the underlying mechanism. MAL2 was overexpressed in EC tissues and cells and its transcription was enhanced by RAD21. Knockdown of MAL2 or RAD21 inhibited malignant behavior and immune evasion of EC cells by repressing MHC-I expression and the cytotoxic effects of CD8 cells. Conversely, MAL2 promoted immune evasion of EC cells and tumor growth in mice in the presence of RAD21 knockdown. These results indicate that RAD21 activation of MAL2 inhibits antigen processing and presentation of MHC-I, thereby inducing immune evasion of EC cells. We further suggest that RAD21 and MAL2 may serve as novel targets for EC immunotherapy.
CD8 T细胞是抗癌免疫的主要介质，调节CD8 T细胞反应一直是癌症免疫治疗的核心焦点。当CD8 T细胞特异性识别肿瘤细胞上由MHC-I呈递的抗原肽时，它们会被激活并杀死肿瘤细胞。然而，肿瘤细胞逃避免疫监视的一个关键机制是减少其抗原呈递。为了确定新的免疫治疗靶点，我们特别关注MAL2在子宫内膜癌（EC）免疫逃逸中的作用及其潜在机制。MAL2在EC组织和细胞中过表达，其转录由RAD21增强。敲低MAL2或RAD21可通过抑制MHC-I表达和CD8细胞的细胞毒性作用来抑制EC细胞的恶性行为和免疫逃逸。相反，在敲低RAD21的情况下，MAL2促进了EC细胞的免疫逃逸和小鼠肿瘤生长。这些结果表明，RAD21对MAL2的激活抑制了MHC-I的抗原加工和呈递，从而诱导了EC细胞的免疫逃逸。我们进一步表明，RAD21和MAL2可能作为EC免疫治疗的新靶点。
