DNA repair defects and implications for immunotherapy

Preservation of the integrity of the genetic code requires a complex machinery to defend against both endogenous and exogenous sources of damage.Multiple repair pathways have been described and are generally divided into those involved in single-strand repair of damaged or mispaired bases (e.g., base excision repair, nucleotide excision repair, direct repair, and mismatch repair pathways), and those involved in repair of DNA double-strand breaks (e.g., homology-dependent recombination, nonhomologous end joining, and the Fanconi anemia pathway).When DNA repair processes fail, damage resulting in somatic mutations in tumor suppressor genes or oncogenes can lead to uncontrolled proliferation and carcinogenesis.Several cancer susceptibility syndromes have been identified that are linked to heritable defects in specific DNA repair pathways and proteins; however, cancers associated with defective DNA repair may occur sporadically as well and defective DNA repair has a critical role in tumor progression (1).Defective DNA repair is highly prevalent in cancers, with a recent analysis of DNA damage repair deficiency across 33 cancer types reporting somatic alterations in approximately one-third of cancers analyzed (2).The presence of such defects in DNA repair pathways in cancers may have therapeutic implications, indicating a potential vulnerability to certain DNA-damaging therapies, such as platinum chemotherapies and inhibitors of poly (ADP-ribose) polymerase (PARP) in the case of BRCA1/2-mutated breast and ovarian cancers and the alkylating agent temozolomide in MGMT-methylated glioblastoma multiforme (3-7).More recently, a role for DNA damage repair pathways in selection of patients for immunotherapy has emerged, and this review will summarize what is known regarding the association between DNA repair defects and the host immune response and tumor susceptibility to immunotherapy.