DNA Repair and Signaling in Immune-Related Cancer Therapy

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.

Immune Signature-Based Risk Stratification and Prediction of Immunotherapy Efficacy for Bladder Urothelial Carcinoma

“…The predictive role of TMB in ICI treatment has been confirmed in many clinical studies (Davoli et al, 2017). Tumor cells with high TMB can produce more tumor-specific antigens and thus can be easily recognized and killed by immune cells (Kakoti et al, 2020). In our OS model, the TMB of the low-risk group was higher and the prognosis of the high-TMB group was remarkably better after the samples were grouped according to TMB.…”

Transformation of a cold to hot tumor and a durable response to immunotherapy in a patient with non-small cell lung cancer after chemoradiotherapy: a case report

“…Studies by Singavi and others have suggested that the amplification of some genes on the human chromosome 11q13, such as CCND1, FGF3, FGF4, and FGF19, may be related to the occurrence of hyper-progression (11). The loss of function of the ATM is related to the autosomal recessive disease ataxia-telangiectasia, hypersensitivity to ionizing radiation, cancer susceptibility, immunodeficiency, and genomic instability, which may indicate better immune efficacy and sensitivity to ionizing radiation (12,13). The loss of PBRM1 may change the overall tumor cell expression profile.…”

Clinical outcomes and longitudinal circulating tumor DNA changes after treatment with nivolumab and olaparib in immunotherapy relapsed melanoma with detected homologous recombination deficiency

“…PARP inhibitors can enhance sensitivity in the tumor microenvironment to ICB through a variety of mechanisms including increased chromosomal aberrations due to deficiency in DNA repair pathways, and modulation of immune response in the tumor microenvironment ( Teo et al 2018 ; Chabanon et al 2019 ). In addition, the presence of HRD in cancer cells as well as the use of PARP inhibitor–induced synthetic lethality could lead to neoantigen formation that may resensitize tumor cells to ICB ( Kakoti et al 2020 ).…”