DNA repair defects and implications for immunotherapy
Katherine M. Bever, Dung T. Le
Katherine M. Bever, Dung T. Le
Published October 1, 2018
Citation Information: J Clin Invest. 2018;128(10):4236-4242. https://doi.org/10.1172/JCI122010.
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DNA repair defects and implications for immunotherapy

Abstract

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.

Authors

Katherine M. Bever, Dung T. Le

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Figure 1

DNA damage combined with failed DNA repair is an initiating step in oncogenesis, but also contributes to ongoing tumor progression with uncontrolled replication and accumulation of genomic errors and genomic instability.

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DNA damage combined with failed DNA repair is an initiating step in onco...
Genomic instability may lead to enhanced tumor immunogenicity through (a) the accumulation of high numbers of mutations, possibly resulting in the expression of mutation-associated neoantigens, which can activate the adaptive immune response, and (b) the accumulation of cytosolic DNA, which can activate the innate immune response via the cGAS/STING pathway. Persistence/progression of these tumors thus relies on mechanisms of immune escape such as PD-(L)1. The addition of DNA-damaging therapies (e.g., chemotherapy, radiation, PARP inhibitors) may further enhance genomic instability and therefore synergize with CPIs in some tumors.