Loss of CMTM6 promotes DNA damage-induced cellular senescence and antitumor immunity.
Loss of CMTM6 promotes DNA damage-induced cellular senescence and antitumor immunity.
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CMTM6的缺失促进DNA损伤诱导的细胞衰老和抗肿瘤免疫
DOI：
10.1080/2162402x.2021.2011673
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发表时间：
2022
期刊：
影响因子：
7.2
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Wang H;Fan Y;Chen W;Lv Z;Wu S;Xuan Y;Wang C;Lu Y;Guo T;Shen D;Zhang F;Huang Q;Gao Y;Li H;Ma X;Wang B;Huang Y;Zhang X
摘要最近的研究表明，趋化素样因子样的Marvel跨膜区家族成员6(CMTM6)通过调节程序性死亡配体1的稳定性来促进肿瘤进展和调节肿瘤免疫，但其在肾透明细胞癌(CcRCC)中的内在功能和调控机制尚不清楚。在这里，我们发现CMTM6在肾细胞癌组织中表达上调，并且与晚期肿瘤分级、早期转移和较差的预后密切相关。在体外和体内异种移植小鼠模型中，CMTM6的缺失显著地损害了ccRCC细胞的增殖、迁移和侵袭。此外，靶向CMTM6促进了抗肿瘤免疫，表现为同基因移植小鼠模型中CD4+和CD8+T细胞的渗透增加。进一步的研究发现，CMTM6的缺失触发了DNA损伤反应的异常激活，导致微核形成和G2/M检查点停滞，最终导致细胞衰老，大量趋化因子和细胞因子强烈上调。我们的发现首次表明，CMTM6在维持癌症基因组稳定和促进肿瘤介导的免疫抑制方面发挥了新的作用，将DNA损伤信号与炎症因子的分泌联系起来。靶向CMTM6可改善晚期肾细胞癌患者的治疗。
ABSTRACT Recent studies have revealed that chemokine-like factor-like MARVEL transmembrane domain-containing family member 6 (CMTM6) promotes tumor progression and modulates tumor immunity by regulating programmed death-ligand 1 stability; however, its intrinsic functions and regulatory mechanisms in clear cell renal cell carcinoma (ccRCC) remain poorly understood. Here, we show that CMTM6 is upregulated in ccRCC tissues and is strongly associated with advanced tumor grades, early metastases, and a worse prognosis. CMTM6 depletion significantly impaired the proliferation, migration, and invasion of ccRCC cells in vitro and in xenograft mouse models in vivo. In addition, targeting CMTM6 promotes anti-tumor immunity, represented by increased infiltration of CD4+ and CD8+ T cells in syngeneic graft mouse models. Further research revealed that loss of CMTM6 triggered aberrant activation of DNA damage response, resulting in micronucleus formation and G2/M checkpoint arrest, finally leading to cellular senescence with robust upregulation of numerous chemokines and cytokines. Our findings show for the first time the novel role of CMTM6 in maintaining cancer genome stability and facilitating tumor-mediated immunosuppression, linking DNA damage signaling to the secretion of inflammatory factors. Targeting CMTM6 may improve the treatment of patients with advanced ccRCC.