DNA repair defects and implications for immunotherapy

A complex DNA repair machinery has evolved to protect genomic integrity in the face of a myriad of DNA damage sources. When DNA repair fails, this damage can lead to carcinogenesis and tumor genomic instability. Indeed, many heritable cancer predisposition syndromes are attributable to germline defects in DNA repair pathways. On the other hand, these defects may also portend particular vulnerabilities of the cancer and may be exploited therapeutically. Most recently this has been demonstrated in the case of mismatch repair-deficient cancers, in which the immune checkpoint inhibitors have been demonstrated to be highly active. This observation has paved the way for further research investigating other sources of genomic instability that may serve as biomarkers to select patients for immunotherapy.