文章：

靶向DNA损伤反应在免疫肿瘤学：发展和机遇

Targeting the DNA damage response in immuno-oncology: developments and opportunities

原文发布日期：2021-08-10

DOI: 10.1038/s41568-021-00386-6

类型: Review Article

开放获取: 否

英文摘要：

Immunotherapy has revolutionized cancer treatment and substantially improved patient outcome with regard to multiple tumour types. However, most patients still do not benefit from such therapies, notably because of the absence of pre-existing T cell infiltration. DNA damage response (DDR) deficiency has recently emerged as an important determinant of tumour immunogenicity. A growing body of evidence now supports the concept that DDR-targeted therapies can increase the antitumour immune response by (1) promoting antigenicity through increased mutability and genomic instability, (2) enhancing adjuvanticity through the activation of cytosolic immunity and immunogenic cell death and (3) favouring reactogenicity through the modulation of factors that control the tumour–immune cell synapse. In this Review, we discuss the interplay between the DDR and anticancer immunity and highlight how this dynamic interaction contributes to shaping tumour immunogenicity. We also review the most innovative preclinical approaches that could be used to investigate such effects, including recently developed ex vivo systems. Finally, we highlight the therapeutic opportunities presented by the exploitation of the DDR–anticancer immunity interplay, with a focus on those in early-phase clinical development.

摘要翻译： 

免疫疗法已经彻底改变了癌症治疗格局，并在多种肿瘤类型中显著改善了患者预后。然而，大多数患者仍未能从这些疗法中获益，这主要归因于肿瘤微环境中缺乏预先存在的T细胞浸润。DNA损伤反应（DDR）缺陷最近已成为决定肿瘤免疫原性的关键因素。越来越多的证据支持这一观点：靶向DDR疗法可通过以下机制增强抗肿瘤免疫反应：（1）通过增加突变率和基因组不稳定性来提升抗原性；（2）通过激活胞质免疫和免疫原性细胞死亡来增强佐剂性；（3）通过调控控制肿瘤-免疫细胞突触的因子来促进反应原性。本文重点探讨DDR与抗肿瘤免疫之间的相互作用机制，阐释这种动态关联如何塑造肿瘤免疫原性。同时综述了可用于研究此类效应的创新临床前方法，包括最新开发的离体培养系统。最后，我们着重分析了利用DDR-抗肿瘤免疫相互作用带来的治疗机遇，重点关注那些处于早期临床开发阶段的研究方向。

原文链接：

Targeting the DNA damage response in immuno-oncology: developments and opportunities