■总结AKT-mTOR信号在调节癌细胞DNA损伤反应和PD-L1表达中的作用,并提出了在癌症免疫治疗时代靶向AKT-mTOR信号结合放射免疫治疗的新策略。
■免疫治疗极大地改善了许多癌症患者的临床结果,并改变了癌症患者管理的格局。然而,只有一小部分癌症患者(约20-30%)受益于基于免疫检查点阻断的免疫疗法.当前的挑战是找到生物标志物来预测患者对免疫疗法的反应以及使患者对免疫疗法敏感的策略。
■搜索并回顾2000-2021年在PUBMED发表的关键词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。已显示放射疗法通过影响全身免疫来减少局部照射的肿瘤以及转移性非照射的肿瘤的生长(远视效应)。始终如一,免疫疗法已被证明可以增强放射疗法,超过一百项癌症类型的放射疗法与免疫疗法(放射免疫疗法)的联合临床试验。然而,现有数据显示放射免疫疗法试验的疗效有限.AKT-mTOR信号传导是主要的肿瘤生长促进途径,并且在大多数癌症中上调。AKT-mTOR信号传导被生长因子以及基因毒性应激(包括放射治疗)激活。重要的是,研究表明,AKT-mTOR是调节肿瘤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通过靶向AKT-mTOR信号与放射免疫疗法组合的新型癌症治疗策略。
OBJECTIVE: 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.
BACKGROUND: 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.
METHODS: 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.
CONCLUSIONS: 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.