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The complementarity of DDR, nucleic acids and anti-tumour immunity.
- Source :
-
Nature [Nature] 2023 Jul; Vol. 619 (7970), pp. 475-486. Date of Electronic Publication: 2023 Jul 19. - Publication Year :
- 2023
-
Abstract
- Immune checkpoint blockade (ICB) immunotherapy is a first-line treatment for selected cancers, yet the mechanisms of its efficacy remain incompletely understood. Furthermore, only a minority of patients with cancer benefit from ICB, and there is a lack of fully informative treatment response biomarkers. Selectively exploiting defects in DNA damage repair is also a standard treatment for cancer, spurred by enhanced understanding of the DNA damage response (DDR). DDR and ICB are closely linked-faulty DDR produces immunogenic cancer neoantigens that can increase the efficacy of ICB therapy, and tumour mutational burden is a good but imperfect biomarker for the response to ICB. DDR studies in ICB efficacy initially focused on contributions to neoantigen burden. However, a growing body of evidence suggests that ICB efficacy is complicated by the immunogenic effects of nucleic acids generated from exogenous DNA damage or endogenous processes such as DNA replication. Chemotherapy, radiation, or selective DDR inhibitors (such as PARP inhibitors) can generate aberrant nucleic acids to induce tumour immunogenicity independently of neoantigens. Independent of their functions in immunity, targets of immunotherapy such as cyclic GMP-AMP synthase (cGAS) or PD-L1 can crosstalk with DDR or the DNA repair machinery to influence the response to DNA-damaging agents. Here we review the rapidly evolving, multifaceted interfaces between DDR, nucleic acid immunogenicity and immunotherapy efficacy, focusing on ICB. Understanding these interrelated processes could explain ICB treatment failures and reveal novel exploitable therapeutic vulnerabilities in cancers. We conclude by addressing major unanswered questions and new research directions.<br /> (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
- Subjects :
- Humans
Antigens, Neoplasm immunology
Antigens, Neoplasm metabolism
DNA Repair
DNA Replication
Mutation
Biomarkers, Tumor
Poly(ADP-ribose) Polymerase Inhibitors pharmacology
Poly(ADP-ribose) Polymerase Inhibitors therapeutic use
DNA Damage
Immunotherapy methods
Immunotherapy trends
Neoplasms genetics
Neoplasms immunology
Neoplasms metabolism
Neoplasms therapy
Nucleic Acids metabolism
Immune Checkpoint Inhibitors pharmacology
Immune Checkpoint Inhibitors therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 619
- Issue :
- 7970
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 37468584
- Full Text :
- https://doi.org/10.1038/s41586-023-06069-6