a. 肿瘤微环境的免疫抑制。在暴露于免疫检查点抑制剂期间,肿瘤细胞发生相关基因的改变,促进上皮-间充质转化,诱导免疫抑制微环境。免疫抑制肿瘤微环境的特征包括:树突状细胞功能和效应T细胞浸润减弱,PD-L1 表达升高,MHC I 表达降低等。b. 有缺陷的抗原处理和呈递。由于 MHC I 或 β2 微球蛋白 B2M 的缺失,肿瘤细胞可能无法呈递抗原,或干扰抗原呈递的其它机制。c. T 细胞耗竭。精疲力竭的 T 细胞分泌较低数量的肿瘤杀伤细胞因子 (如 IL-2、TNF-α 和 IFN-γ),并表现出增殖能力降低、细胞毒性低和抗肿瘤免疫反应降低。
小结人类和癌症的对抗已经从关注细胞毒性疗法转向增强抗肿瘤免疫。事实上除了文中提到的免疫检查点抑制和靶向肿瘤微环境中的可溶性介质,许多针对非小细胞肺癌的疫苗在过去十年中也进行了大规模的 III 期试验,用于增强 T 细胞对特异性肿瘤抗原的反应。免疫疗法在全世界范围内延长了癌症患者的生命,但治疗耐受问题也不容忽视。但是有理由相信,相比于简单粗暴的“一刀切”式化疗,调节人体自我防御功能的免疫疗法以及联合疗法将会为癌症患者带去更大的生机!
Vactosertib (EW-7197) 是一种有效的,具有口服活性且具有 ATP 竞争性激活素受体样激酶 5 (ALK5) 抑制剂,具有强大的抗转移活性和抗癌作用。
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