Ye Di, Zhou Shuang, Dai Xinyu, Xu Huanji, Tang Qiulin, Huang Huixi, Bi Feng
Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China.
Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China.
Biochim Biophys Acta Rev Cancer. 2024 Sep;1879(5):189161. doi: 10.1016/j.bbcan.2024.189161. Epub 2024 Aug 2.
Immune checkpoint blockade (ICB) therapy has achieved broad applicability and durable clinical responses across cancer types. However, the overall response rate remains suboptimal because some patients do not respond or develop drug resistance. The low infiltration of CD8 cytotoxic T cells (CTLs) in the tumor microenvironment due to insufficient antigen presentation is closely related to the innate resistance to ICB. The duration and spatial distribution of major histocompatibility complex class I (MHC-I) expression on the cell surface is critical for the efficient presentation of endogenous tumor antigens and subsequent recognition and clearance by CTLs. Tumor cells reduce the surface expression of MHC-I via multiple mechanisms to impair antigen presentation pathways and evade immunity and/or develop resistance to ICB therapy. As an increasing number of studies have focused on membrane MHC-I trafficking and degradation in tumor cells, which may impact the effectiveness of tumor immunotherapy. It is necessary to summarize the mechanism regulating membrane MHC-I translocation into the cytoplasm and degradation via the lysosome. We reviewed recent advances in the understanding of endosomal-lysosomal MHC-I transport and highlighted the means exploited by tumor cells to evade detection and clearance by CTLs. We also summarized new therapeutic strategies targeting these pathways to enhance classical ICB treatment and provide new avenues for optimizing cancer immunotherapy.
免疫检查点阻断（ICB）疗法已在多种癌症类型中获得广泛应用并产生持久的临床反应。然而，总体反应率仍不尽人意，因为一些患者无反应或产生耐药性。由于抗原呈递不足导致肿瘤微环境中CD8细胞毒性T细胞（CTL）浸润较低，这与对ICB的固有抗性密切相关。细胞表面主要组织相容性复合体I类（MHC-I）表达的持续时间和空间分布对于内源性肿瘤抗原的有效呈递以及随后CTL的识别和清除至关重要。肿瘤细胞通过多种机制降低MHC-I的表面表达，以损害抗原呈递途径并逃避免疫和/或对ICB治疗产生抗性。随着越来越多的研究聚焦于肿瘤细胞中膜MHC-I的转运和降解，这可能会影响肿瘤免疫治疗的效果。有必要总结调节膜MHC-I转运至细胞质并通过溶酶体降解的机制。我们综述了对内体-溶酶体MHC-I转运的最新认识进展，并强调了肿瘤细胞用于逃避免疫细胞毒性T淋巴细胞检测和清除的手段。我们还总结了针对这些途径的新治疗策略，以增强经典ICB治疗，并为优化癌症免疫治疗提供新途径。
