Shen Changxian, He Yuqi, Chen Qiang, Feng Haihua, Williams Terence M, Lu Yuanzhi, He Zhengfu
Department of Radiation Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
Monash School of Medicine, Monash University, Clayton, VIC, Australia.
Ann Transl Med. 2021 Oct;9(20):1596. doi: 10.21037/atm-21-4544.
To summarize the roles of AKT-mTOR signaling in the regulation of the DNA damage response and PD-L1 expression in cancer cells, and propose a novel strategy of targeting AKT-mTOR signaling in combination with radioimmunotherapy in the era of cancer immunotherapy.
Immunotherapy has greatly improved the clinical outcomes of many cancer patients and has changed the landscape of cancer patient management. However, only a small subgroup of cancer patients (~20-30%) benefit from immune checkpoint blockade-based immunotherapy. The current challenge is to find biomarkers to predict the response of patients to immunotherapy and strategies to sensitize patients to immunotherapy.
Search and review the literature which were published in PUBMED from 2000-2021 with the key words mTOR, AKT, drug resistance, DNA damage response, immunotherapy, PD-L1, DNA repair, radioimmunotherapy.
More than 50% of cancer patients receive radiotherapy during their course of treatment. Radiotherapy has been shown to reduce the growth of locally irradiated tumors as well as metastatic non-irradiated tumors (abscopal effects) by affecting systemic immunity. Consistently, immunotherapy has been demonstrated to enhance radiotherapy with more than one hundred clinical trials of radiation in combination with immunotherapy (radioimmunotherapy) across cancer types. Nevertheless, current available data have shown limited efficacy of trials testing radioimmunotherapy. AKT-mTOR signaling is a major tumor growth-promoting pathway and is upregulated in most cancers. AKT-mTOR signaling is activated by growth factors as well as genotoxic stresses including radiotherapy. Importantly, recent advances have shown that AKT-mTOR is one of the main signaling pathways that regulate DNA damage repair as well as PD-L1 levels in cancers. These recent advances clearly suggest a novel cancer therapy strategy by targeting AKT-mTOR signaling in combination with radioimmunotherapy.
总结AKT-mTOR信号通路在调控癌细胞DNA损伤反应及PD-L1表达中的作用，并提出在癌症免疫治疗时代，联合放射免疫疗法靶向AKT-mTOR信号通路的新策略。
免疫疗法极大地改善了许多癌症患者的临床结局，改变了癌症患者的治疗格局。然而，只有一小部分癌症患者（约20%-30%）能从基于免疫检查点阻断的免疫疗法中获益。当前的挑战是寻找预测患者对免疫疗法反应的生物标志物以及使患者对免疫疗法敏感的策略。
检索并综述2000年至2021年发表在PUBMED上的文献，关键词为mTOR、AKT、耐药性、DNA损伤反应、免疫疗法、PD-L1、DNA修复、放射免疫疗法。
超过50%的癌症患者在治疗过程中接受放疗。放疗已被证明可通过影响全身免疫来减少局部照射肿瘤以及转移性未照射肿瘤的生长（远隔效应）。同样，免疫疗法已通过针对多种癌症类型的一百多项放疗联合免疫疗法（放射免疫疗法）临床试验被证明可增强放疗效果。然而，目前可用数据显示放射免疫疗法试验的疗效有限。AKT-mTOR信号通路是主要的肿瘤生长促进通路，在大多数癌症中上调。AKT-mTOR信号通路被生长因子以及包括放疗在内的基因毒性应激激活。重要的是，最近的进展表明AKT-mTOR是调节癌症中DNA损伤修复以及PD-L1水平的主要信号通路之一。这些最新进展清楚地表明了一种联合放射免疫疗法靶向AKT-mTOR信号通路的新型癌症治疗策略。
