Targeting DNA Damage Response and Repair Genes to Enhance Anticancer Immunotherapy: Rationale and Clinical Implication

Abstract

DNA damage response and repair ( DDR) genes play a central role in the life of actively replicating cells, cooperating to maintenance of genomic integrity. However, exogenous or endogenous factors, including deficiency in DDR genes, can cause different degrees of DNA damage that profoundly impacts the tumor immunogenicity and enhance antitumor immune response through neoantigen-dependent and neoantigen-independent mechanisms. Inhibition of DDRs is already an effective therapeutic strategy in different cancer types. In addition, because DDR inhibition can also induce and amplify DNA damage in cancer cells, with a deep impact on antitumor immune responses, combining DDR inhibitors with immune checkpoint inhibitors represent an attractive therapeutic strategy to potentially improve the clinical outcomes of patients with metastatic cancer. In this review, we provide an overview of the rational and potential of combining DDR and immune checkpoint inhibition to exploit the enhanced antitumor immune response induced by DNA damage.

Hacking Pancreatic Cancer: Present and Future of Personalized Medicine

“…DDR deficiency is known to co-segregate with improved response to platinum derivatives consistently with the mechanism of action of these agents. Moreover, deficient DDR machinery can enhance an immune response in multiple ways, providing the rationale for the combination of DDR-targeting agents and immunotherapy [ 22 ]. The number of antitumor agents taking advantage of DDR deficiency is constantly expanding and many trials are ongoing ( Table 1 ), hopefully to provide increasing treatment possibilities for PC patients.…”

Expression of immune checkpoint PD‑1 in non‑small cell lung cancer is associated with tumor cell DNA‑dependent protein kinase

“…Furthermore, it has been reported that pathogenic DNA damage response (DDR) and repair mutations are associated with improved treatment response rate, progression-free survival, and overall survival in patients with NSCLC treated with programmed death ligand 1 [PD-(L)1] inhibitor therapy ( 17 ). Therefore, it is suggested that combining DDR inhibitors with DNA damaging agents, or PD-1 blockade can enhance the overall DNA damage and induce a more sustained upregulation of the cGAS-STING pathway and consequently the production of Th1 cytokines ( 18 ).…”

“…It has been demonstrated that an ability of cancer cells to repair therapeutically induced DNA damage has extensive impacts on anti-cancer therapeutic efficacy ( 19 ). Moreover, since DDR inhibition can also induce and amplify DNA damage in cancer cells, combining DDR inhibitors with immune checkpoint inhibitors and/or cytotoxic therapies represents an attractive strategy to improve patient outcomes ( 18 ).…”

Analyzing the Opportunities to Target DNA Double-Strand Breaks Repair and Replicative Stress Responses to Improve Therapeutic Index of Colorectal Cancer

“…Of all DDR and DNA repair pathways, genes involved with the repair of DNA double-strand breaks (DSBs) are somatically mutated in up to 20% of CRC [54,55]. Fortunately, evolving evidence obtained from large database analyses of CRC tumors have identified DDR-based signatures, which may underpin for the eligibility of treatment with novel (e.g., inhibitors of ATR, CHK1, WEE1, and ATM), and marketed DNA repair inhibitors (e.g., PARP inhibitors), and immunotherapy [56]. Although MMR deficiency remains the unique relevant DDR-based signature for CRC prognosis and response to therapy, the identification of deficiencies in other DNA repair pathways may unveil mutational signatures and provide insights into new targets.…”