Targeting DNA Damage Repair for Immune Checkpoint Inhibition: Mechanisms and Potential Clinical Applications.

Wei Sun,Qing Zhang,Lin Yang,Yue Sun,Yang Li,Runkun Wang

doi:10.3389/fonc.2021.648687

Abstract

DNA damage repair (DDR) pathways play an essential role in maintaining genomic integrity. DDR dysfunction leads to accumulated DNA damage, predisposition to cancer, and high sensitivity to chemotherapy and radiotherapy. Recent studies have demonstrated that DDR status is associated with response to immune checkpoint inhibitors (ICIs). Among the DDR pathways, mismatch repair is one of the most recognized predictive biomarkers for ICIs. Furthermore, preclinical and early clinical studies suggest the rationale of combining agents targeting the DDR pathways, such as poly (ADP-ribose) polymerase (PARP) inhibitors, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, and ataxia telangiectasia and rad3-related (ATR) kinase inhibitors, with ICIs. In the present review, we describe the predictive role of DDR pathways in ICIs and summarize the advances in potential combination strategies of novel agents targeting DDR with ICIs for cancer treatment.

Highlights

Immunotherapy, especially immune checkpoint inhibition (ICI), has reshaped the cancer treatment landscape and has become a standard therapy for multiple cancer types owing to its robust and durable anti-tumor response [1,2,3]
Emerging evidence supports that alterations in the DNA damage repair (DDR) pathways play potential predictive roles for ICIs
The combination of agents targeting DDR with ICIs has resulted in appealing anti-tumor effects in preclinical and clinical studies

Summary

INTRODUCTION

Immunotherapy, especially immune checkpoint inhibition (ICI), has reshaped the cancer treatment landscape and has become a standard therapy for multiple cancer types owing to its robust and durable anti-tumor response [1,2,3]. In terms of the mechanism, PARP inhibitors inhibit DNA repair and aggravate DNA damage, which induces neoantigens and cytosolic DNA, activates the interferon pathway, triggers anti-tumor immunity, and converts immunologically “cold” tumors to “hot” tumors They could sensitize tumor cells to ICIs, especially under a BRCA-deficient background [55, 56]. This study suggests that both biomarkers for PARP inhibitors and ICIs should be considered to predict the response to the combinational treatment Another focus of ovarian cancer is maintenance therapy using PARP inhibitors combined with ICIs. Three phase 3 randomized, double-blind, placebo-controlled multicenter studies have explored the effect of chemotherapy ± anti-PD-1/ anti-PD-L1 followed by maintenance with anti-PD-L1 and olaparib/niraparib in newly diagnosed advanced ovarian cancer (NCT03737643/DUO-O), BRCA non-mutated advanced epithelial ovarian cancer (NCT03740165/KEYLYNK-001/ ENGOT-ov43), and recurrent ovarian, tubal, or peritoneal cancer (NCT03598270).

Trial registration number

Findings

CONCLUSIONS AND REMAINING CHALLENGES