Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China.
BioBox Sciences, Inc, Guangzhou, China.
Oncogene. 2021 Mar;40(12):2230-2242. doi: 10.1038/s41388-021-01689-6. Epub 2021 Mar 1.
Despite the well-established role of CMTM6 in the stabilization of cell surface PD-L1 in cancer cells, the mechanisms underlying CMTM6 expression and regulation are still largely unknown. Here we unexpectedly find a strikingly positive correlation between CMTM6 and Hu-Antigen R (HuR) expression in most types of cancer. Mechanistically, we elucidate HuR stabilizes CMTM6 mRNA via direct association with AU-rich elements (AREs) in its 3'UTR and predominantly up-regulates CMTM6, which is readily abolished by HuR-specific inhibitor, MS-444. Phenotypically, we notice abundant cell surface PD-L1 in HuR-high cancer cells, which significantly inhibits immune activation of co-cultured T cells as indicated by IL-2 production. Treatment with MS-444 completely relieves immune suppression imposed by HuR-overexpression and further stimulates immune responses. Ectopic HuR accelerates allograft tumor progression in vivo, which is greatly compromised by simultaneous administration with MS-444. Our study uncovers a novel mechanism in control of CMTM6 and therefore PD-L1 expression, and suggests the potential of combining HuR inhibitor with PD-1/PD-L1 antibodies for cancer immunotherapy.
尽管 CMTM6 在稳定癌细胞表面 PD-L1 方面的作用已得到充分证实，但 CMTM6 表达和调控的机制在很大程度上仍然未知。在这里，我们出人意料地发现，CMTM6 与 Hu 抗原 R（HuR）在大多数类型的癌症中的表达之间存在显著的正相关。在机制上，我们阐明了 HuR 通过与 3'UTR 中的富含 AU 的元件（AREs）直接结合来稳定 CMTM6 mRNA，并主要上调 CMTM6，而 HuR 特异性抑制剂 MS-444 可显著抑制 CMTM6 的表达。表型上，我们注意到 HuR 高表达的癌细胞表面有大量的 PD-L1，这显著抑制了共培养的 T 细胞的免疫激活，表现为 IL-2 的产生减少。用 MS-444 处理可完全解除 HuR 过表达引起的免疫抑制，并进一步刺激免疫反应。外源性 HuR 可加速体内同种异体肿瘤的进展，而同时给予 MS-444 则可大大削弱这一进程。我们的研究揭示了控制 CMTM6 以及因此 PD-L1 表达的新机制，并提示了将 HuR 抑制剂与 PD-1/PD-L1 抗体联合用于癌症免疫治疗的潜力。
