Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310018, China; Cancer Center of Zhejiang University, Hangzhou 310058, China.
Biochem Pharmacol. 2023 Sep;215:115724. doi: 10.1016/j.bcp.2023.115724. Epub 2023 Jul 29.
Anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) antibodies have developed rapidly but exhibited modest activity in ovarian cancer (OC), achieving a clinical response rate ranging from 5.9% to 19%. Current evidence indicate that the establishment of an integrated cancer-immunity cycle is a prerequisite for anti-PD-1/PD-L1 antibodies. Any impairment in this cycle, including lack of cancer antigens release, impaired antigen-presenting, decreased T cell priming and activation, less T cells that are trafficked or infiltrated in tumor microenvironment (TME), and low tumor recognition and killings, will lead to decreased infiltrated cytotoxic T cells to tumor bed and treatment failure. Therefore, combinatorial strategies aiming to modify cancer-immunity cycle and reprogram tumor immune microenvironment are of great interest. By far, various strategies have been studied to enhance responsiveness to PD-1/PD-L1 inhibitors in OC. Platinum-based chemotherapy increases neoantigens release; poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) improve the function of antigen-presenting cells and promote the trafficking of T cells into tumors; epigenetic drugs help to complete the immune cycle by affecting multiple steps; immunotherapies like anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies reactivate T cells, and other treatment strategies like radiotherapy helps to increase the expression of tumor antigens. In this review, we will summarize the preclinical studies by analyzing their contribution in modifying the cancer immunity cycle and remodeling tumor environment, and we will also summarize recent progress in clinical trials and discuss some perspectives to improve these treatment strategies.
抗程序性细胞死亡蛋白 1/程序性细胞死亡配体 1（抗 PD-1/PD-L1）抗体发展迅速，但在卵巢癌（OC）中的活性中等，临床反应率为 5.9%至 19%。目前的证据表明，建立一个综合的癌症免疫循环是抗 PD-1/PD-L1 抗体的前提。这个循环中的任何障碍，包括缺乏癌症抗原释放、抗原呈递受损、T 细胞初始激活减少、在肿瘤微环境（TME）中运输或浸润的 T 细胞减少，以及肿瘤识别和杀伤能力降低，都会导致浸润到肿瘤床的细胞毒性 T 细胞减少，从而导致治疗失败。因此，旨在修饰癌症免疫循环和重新编程肿瘤免疫微环境的联合策略具有很大的意义。迄今为止，已经研究了各种策略来提高 OC 中对 PD-1/PD-L1 抑制剂的反应性。铂类化疗增加了新抗原的释放；聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi）改善了抗原呈递细胞的功能，并促进了 T 细胞向肿瘤的运输；表观遗传药物通过影响多个步骤有助于完成免疫循环；抗细胞毒性 T 淋巴细胞抗原 4（CTLA-4）抗体等免疫疗法重新激活 T 细胞，其他治疗策略如放疗有助于增加肿瘤抗原的表达。在这篇综述中，我们将通过分析它们在修饰癌症免疫循环和重塑肿瘤环境方面的贡献，总结临床前研究，并讨论一些改善这些治疗策略的观点。
