DNA Repair and Signaling in Immune-Related Cancer Therapy

Sangeeta Kakoti; Hiro Sato; Siddhartha Laskar; Takaaki Yasuhara; Atsushi Shibata

doi:10.3389/fmolb.2020.00205

DNA Repair and Signaling in Immune-Related Cancer Therapy

Front Mol Biosci. 2020 Sep 8:7:205. doi: 10.3389/fmolb.2020.00205. eCollection 2020.

Authors

Sangeeta Kakoti^{1

2}, Hiro Sato², Siddhartha Laskar³, Takaaki Yasuhara^{4

5}, Atsushi Shibata¹

Affiliations

¹ Signal Transduction Program, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Japan.
² Department of Radiation Oncology, Gunma University, Maebashi, Japan.
³ Department of Radiation Oncology, Tata Memorial Centre, Mumbai, India.
⁴ Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁵ Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, United States.

Abstract

Cancer therapy using immune checkpoint inhibitors (ICIs) is a promising clinical strategy for patients with multiple types of cancer. The expression of programmed cell death ligand-1 (PD-L1), an immune-suppressor ligand, in cancer cells is a factor that influences the efficacy of ICI therapy, particularly in the anti-programmed cell death protein-1 (PD-1)/PD-L1 antibody therapy. PD-L1 expression in cancer cells are associated with tumor mutation burden including microsatellite instability because the accumulation of mutations in the cancer genome can produce abnormal proteins via mutant mRNAs, resulting in neoantigen production and HLA-neoantigen complex presentation in cancer cells. HLA-neoantigen presentation promotes immune activity within tumor environment; therefore, known as hot tumor. Thus, as the fidelity of DNA repair affects the generation of genomic mutations, the status of DNA repair and signaling in cancer cells can be considered prior to ICI therapy. The Cancer Genome Atlas (TCGA) and The Cancer Immunome Atlas (TCIA) database analysis showed that tumor samples harboring mutations in any non-homologous end joining, homologous recombination, or DNA damage signaling genes exhibit high neoantigen levels. Alternatively, an urgent task is to understand how the DNA damage-associated cancer treatments change the status of immune activity in patients because multiple clinical trials on combination therapy are ongoing. Recent studies demonstrated that multiple pathways regulate PD-L1 expression in cancer cells. Here, we summarize the regulation of the immune response to ICI therapy, including PD-L1 expression, and also discuss the potential strategies to improve the efficacy of ICI therapy for poor responders from the viewpoint of DNA damage response before or after DNA damage-associated cancer treatment.

Keywords: DNA repair; ataxia telangiectasia and Rad3-related; ataxia-telangiectasia-mutated; homologous recombination; immune checkpoint inhibitor; non-homologous end joining.