Alterations of DNA damage response pathway: Biomarker and therapeutic strategy for cancer immunotherapy

Abstract

Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, upregulate the expression of programmed death ligand 1 (PD-L1) and interact with signaling such as cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. Here, we review the basic knowledge of DDR pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.

Keywords: ATM, ataxia-telangiectasia mutated; ATR, ataxia telangiectasia and Rad3 related; BAP1, BRCA1-associated protein 1; BER, base excision repair; BRAF, v-RAF murine sarcoma viral oncogene homologue B; BRCA, breast cancer susceptibility gene; CHEK, cell-cycle checkpoint kinase; CHK1, checkpoint kinase 1; DAMP, damage-associated molecular patterns; DDR, DNA damage response; DNA damage response; DNA repair; DR, direct repair; DSBs, double-strand breaks; FDA, United State Food and Drug Administration; GSK3β, glycogen synthase kinase 3β; Genomic instability; HMGB1, high mobility group box-1; HRR, homologous recombination repair; ICI, immune checkpoint inhibitor; IFNγ, interferon gamma; IHC, immunohistochemistry; IRF1, interferon regulatory factor 1; Immunotherapy; JAK, Janus kinase; MAD1, mitotic arrest deficient-like 1; MGMT, O6-methylguanine methyltransferase; MLH1, MutL homolog 1; MMR, mismatch repair; MNT, MAX network transcriptional repressor; MSH2/6, MutS protein homologue-2/6; MSI, microsatellite instability; MUTYH, MutY homolog; MyD88, myeloid differentiation factor 88; NEK1, NIMA-related kinase 1; NER, nucleotide excision repair; NGS, next generation sequencing; NHEJ, nonhomologous end-joining; NIMA, never-in-mitosis A; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PALB2, partner and localizer of BRCA2; PARP, poly-ADP ribose polymerase; PCR, polymerase chain reaction; PD-1; PD-1, programmed death 1; PD-L1; PD-L1, programmed death ligand 1; PFS, progression-free survival; RAD51C, RAD51 homolog C; RB1, retinoblastoma 1; RPA, replication protein A; RSR, replication stress response; SCNAs, somatic copy number alterations; STAT, signal transducer and activator of transcription; STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1; TILs, tumor-infiltrating lymphocytes; TLR4, Toll-like receptor 4; TMB, tumor mutational burden; TME, tumor microenvironment; TP53, tumor protein P53; TRIF, Toll-interleukin 1 receptor domain-containing adaptor inducing INF-β; Tumor microenvironment; XRCC4, X-ray repair cross complementing protein 4; cGAS, cyclic GMP–AMP synthase; cGAS–STING; ssDNA, single-stranded DNA.

Graphical abstract

Figure 1

The components and mechanisms of DDR pathway. DNA damage may occur from either endogenous or exogenous sources, which can impair genomic instability. Therefore, DNA repair is crucial for maintaining genome stability. Multiple mechanisms involve DNA damage response (DDR) system: direct repair (DR), base excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER), homologous recombination repair (HRR) and nonhomologous end-joining (NHEJ).

Figure 2

Impacts of DDR alterations on immune system in cancers. (A) Correlations of DNA damage and repair with STING pathway in tumor microenvironment. The STING pathway can be activated by DNA damaging agents or DDR alterations. Cytosolic DNA sensor cGAS can activate innate immune responses by catalyzing cGAMP synthesis, which roles as a second messenger in the activation of STING pathway. The activation of STING pathway makes a conformation change of STING, which leads to an endoplasmic reticulum to perinuclear endosome shuttling. TBK1 can phosphorylate STING as well as IRF3, therefore, promoting the production of type I IFNs. Besides, expression of RAE1 can activate NK cells. A hypothesis regarding the mechanisms of STING in spontaneous anti-tumor immunity has been put forward: dying tumor cells are engulfed by DCs, while free tumor DNA is recognized by cGAS, leading to the secretion of IFN α/β to improve DCs' cross-presentation to enhance T cell activation. DNA damage in tumor cells can also cause the activation of natural-killer cells mediated by the expression of retinoic acid early transcript 1 (RAE1) through STING pathway. (B) DDR deficiencies improve tumor recognition through generating neoantigens. The neoantigen hypothesis is that a non-synonymous mutation leads to the change of an amino acid, which produces a new peptide. Therefore, cancer cells with DDR-deficiency can be recognized as the foreign by immune system. (C) DNA damage signaling and DDR deficiencies role as important regulators in upregulating PD-L1 expression. Abbreviations: ATP, adenosine-triphosphate; cGAMP, cyclic GMP–AMP; cGAS, cyclic GMP–AMP synthase; DDR, DNA damage response; DC, dendritic cell; ds DNA, double-stranded DNA; ER, endoplasmic reticulum; GTP, guanosine triohosphte; IRF3, interferon regulatory factor 3, IFN, interferon; NF-κB, nuclear factor kappa-B; NKG2D, natural killer group 2 member D; NK, natural killer; RAE1, retinoic acid early transcript 1; STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1.

Figure 3

Clinical trials of the efficacy of ICIs in tumors with DDR pathway alterations.

Figure 4

Therapeutic strategy of DDR alterations in cancer immunotherapy. Combination strategy: cancer cells treated with PARP inhibitors are sensitive to immune checkpoint inhibitors. PARP inhibitors increase genomic instability, activate immune pathway and upregulate the expression of PD-L1 on cancer cells, making the combination of PARP inhibitor with ICIs a promising strategy against cancer.