Unité INSERM U753, Institut Gustave Roussy, Villejuif, France.
Autophagy. 2012 Apr;8(4):704-6. doi: 10.4161/auto.19572. Epub 2012 Apr 1.
A major challenge in formulating an effective immunotherapy is to overcome the mechanisms of tumor escape from immunosurveillance. We showed that hypoxia-induced autophagy impairs cytotoxic T-lymphocyte (CTL)-mediated tumor cell lysis by regulating phospho-STAT3 in target cells. Autophagy inhibition in hypoxic cells decreases phospho-STAT3 and restores CTL-mediated tumor cell killing by a mechanism involving the ubiquitin proteasome system and SQSTM1/p62. Simultaneously boosting the CTL-response, using a TRP-peptide vaccination strategy, and targeting autophagy in hypoxic tumors, improves the efficacy of cancer vaccines and promotes tumor regression in vivo. Overall, in addition to its immunosuppressive effect, the hypoxic microenvironment also contributes to immunoresistance and can be detrimental to antitumor effector cell functions.
制定有效免疫疗法的主要挑战是克服肿瘤逃避免疫监视的机制。我们表明，缺氧诱导的自噬通过调节靶细胞中的磷酸化 STAT3 来损害细胞毒性 T 淋巴细胞（CTL）介导的肿瘤细胞裂解。在缺氧细胞中抑制自噬会降低磷酸化 STAT3，并通过涉及泛素蛋白酶体系统和 SQSTM1/p62 的机制恢复 CTL 介导的肿瘤细胞杀伤。同时，使用 TRP 肽疫苗接种策略增强 CTL 反应，并针对缺氧肿瘤中的自噬，可提高癌症疫苗的疗效并促进体内肿瘤消退。总的来说，除了其免疫抑制作用外，缺氧微环境也有助于免疫抵抗，并可能对抗肿瘤效应细胞功能有害。
