Crosstalk between immune checkpoint and DNA damage response inhibitors for radiosensitization of tumors

Abstract

Purpose This review article is intended to provide a perspective overview of potential strategies to overcome radiation resistance of tumors through the combined use of immune checkpoint and DNA repair inhibitors. Methods A literature search was conducted in PubMed using the terms (“DNA repair* and DNA damage response* and intracellular immune response* and immune checkpoint inhibition* and radio*”) until January 31, 2023. Articles were manually selected based on their relevance to the topics analyzed. Results Modern radiotherapy offers a wide range of options for tumor treatment. Radiation-resistant subpopulations of the tumor pose a particular challenge for complete cure. This is due to the enhanced activation of molecular defense mechanisms that prevent cell death because of DNA damage. Novel approaches to enhance tumor cure are provided by immune checkpoint inhibitors, but their effectiveness, especially in tumors without increased mutational burden, also remains limited. Combining inhibitors of both immune checkpoints and DNA damage response with radiation may be an attractive option to augment existing therapies and is the subject of the data summarized here. Conclusion The combination of tested inhibitors of DNA damage and immune responses in preclinical models opens additional attractive options for the radiosensitization of tumors and represents a promising application for future therapeutic approaches.

Destabilizing the genome as a therapeutic strategy to enhance response to immune checkpoint blockade: a systematic review of clinical trials evidence from solid and hematological tumors

“…Interestingly, DNA glycosylases may play critical role in epigenetics, in previous studies, DNA glycosylase (TDG) knockouts display an embryonic lethal phenotype as TDG is believed to has critical epigenetic function in DNA methylations ( Ermolaeva et al, 2013 ; Minko et al, 2020 ). Mismatch repair (MMR) is considered as excision-based repair system, and plays a critical role in repairing DNA replication errors and maintaining genomic stability ( Classen et al, 2023 ). It has the ability to eliminate insertion or deletion loops and base-base mismatches that can occur during DNA synthesis.…”

“…Germline mutations in the DNA MMR pair gene homologue hMLH1 has been linked with herited non-polyposis colon cancer ( Morrison et al, 1994 ), also mutations in other MMR genes have been linked to sporadic colorectal ( Poulogiannis et al, 2010 ) and gastric cancers ( Leite et al, 2011 ). Nucleotide excision repair (NER) eliminate a single-stranded DNA molecule that contains short damaged 24–30 base pairs ( Classen et al, 2023 ). It has a central role in recognizing lesions in double helix conformation which can be caused either by UV light or chemical agents that can give rise to DNA adducts.…”

“…In the post-synapsis, when DNA is synthesized Rad51 dissociates from dsDNA to expose the 3′-OH required for DNA synthesis. Thus, targeting these DRR pathways can enhance response to immunotherapeutic agents ( Classen et al, 2023 ; Hodson et al, 2023 ).…”

Effective Radiosensitization of HNSCC Cell Lines by DNA-PKcs Inhibitor AZD7648 and PARP Inhibitors Talazoparib and Niraparib

“…Most SSBs are repaired, the reparation process being carried out by the SSB repair system [ 14 , 21 ], while repairing DSBs is more complex. The two major systems of DDR to repair DSBs are the highly precise homologous recombination (HR) and non-homologous end-joining (NHEJ), which is more error-prone [ 17 , 22 , 23 ], since it ligates broken DNA ends together without a template [ 15 , 16 , 17 , 22 , 24 , 25 ]. Tumor cells are often HR-deficient and heavily rely on NHEJ for DSB repair, since impaired DDR and especially DSB repair results in genomic instability, which is a hallmark of cancer [ 19 , 21 , 26 , 27 , 28 , 29 ].…”