Regulation of programmed death-ligand 1 expression in response to DNA damage in cancer cells: Implications for precision medicine

Abstract

Anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy, which is one of the most promising cancer therapies, is licensed for treating various tumors. Programmed death-ligand 1, which is expressed on the surface of cancer cells, leads to the inhibition of T lymphocyte activation and immune evasion if it binds to the receptor PD-1 on CTLs. Anti-PD-1/PD-L1 Abs inhibit interactions between PD-1 and PD-L1 to restore antitumor immunity. Although certain patients achieve effective responses to anti-PD-1/PD-L1 therapy, the efficacy of treatment is highly variable. Clinical trials of anti-PD-1/PD-L1 therapy combined with radiotherapy/chemotherapy are underway with suggestive evidence of favorable outcome; however, the molecular mechanism is largely unknown. Among several molecular targets that can influence the efficacy of anti-PD-1/PD-L1 therapy, PD-L1 expression in tumors is considered to be a critical biomarker because there is a positive correlation between the efficacy of combined treatment protocols and PD-L1 expression levels. Therefore, understanding the mechanisms underlying the regulation of PD-L1 expression in cancer cells, particularly the mechanism of PD-L1 expression following DNA damage, is important. In this review, we consider recent findings on the regulation of PD-L1 expression in response to DNA damage signaling in cancer cells.

Keywords: DNA damage; clinical protocol; combined modality therapy; cytotoxic T lymphocyte; signal transduction.

Figure 1

Orchestration of double‐strand break (DSB) repair and its associated signaling activity. DSBs are repaired by non‐homologous end joining (NHEJ) or homologous recombination (HR). NHEJ repairs DSBs throughout the cell cycle except for M phase in mammalian cells, whereas HR functions only in S/G₂ phase following DNA replication. DSB ends undergoing NHEJ, which are not resected, activate ataxia‐telangiectasia mutated (ATM). In contrast, DSB ends that undergo resection by DNA nucleases promote HR. The Ku70/80 (Ku) and DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs) complex binds to most DSB ends to protect them from DNA nucleases and thereby promote NHEJ. In G₁ phase, an ATM/p53‐dependent pathway activates G₁/S checkpoint arrest, whereas in G₂ phase, ataxia telangiectasia and Rad3 related (ATR)/checkpoint kinase (Chk1) activates G₂/M checkpoint arrest. As ATM is required for resection, ATM contributes to G₂/M checkpoint arrest. RPA, replication protein A

Figure 2

Regulation of programmed death‐ligand 1 (PD‐L1) expression in the context of DNA damage‐induced signaling in cancer cells. PD‐L1 expression is differentially regulated by neoantigens, cyclic GMP‐AMP synthase (cGAS)/stimulator of interferon genes (STING), ataxia telangiectasia and Rad3 related (ATR)/checkpoint kinase (Chk1), and the damage‐associated molecular pattern pathways in cancer cells. ATM, ataxia‐telangiectasia mutated; DSB, double‐strand break; ER, endoplasmic reticulum; HR, homologous recombination; IFN, interferon; IFNAR, interferon alpha/beta receptor; IFNGR, interferon gamma receptor; IRF, interferon regulatory factor

Figure 3

Release of G₂/M checkpoint arrest with unrepaired double‐strand breaks (DSBs) causes micronuclei or mitotic catastrophe in the next G₁ phase. Cells with intact G₂/M checkpoint machinery are able to arrest the cell cycle phase until most DSBs are repaired; however, as G₂/M checkpoint arrest in human cells is insensitive, particularly in cancer cells, G₂ cells commence progression into M phase with 10‐20 DSBs, resulting in the formation of micronuclei. In contrast, cells with ataxia telangiectasia and Rad3 related (ATR)/checkpoint kinase (Chk1) deficiency progress to M phase without checkpoint arrest and insufficient time for optimal repair. The failure of G₂/M checkpoint arrest causes severe DNA fragmentation during M phase, which result in multiple micronuclei. Such cells harboring multiple nuclear fragmentations are categorized as undergoing mitotic catastrophe

Figure 4

Chronology of the regulation of immune reactions induced by DNA damage‐dependent cellular responses. After DNA damage, cell cycle progression is arrested at the G₂/M checkpoint. For example, 48‐72 h after exposure to 10‐Gy X‐rays, G₂/M checkpoint arrest is released and G₂ cells progress into M phase with double‐strand breaks, followed by the formation of micronuclei in the next G₁. Finally, cancer cells receive a lethal dose of DNA damage. The upregulation of programmed death‐ligand 1 (PD‐L1) expression is induced in each process, although through distinct molecular mechanisms. Thus, anti‐PD‐1/PD‐L1 therapy could be given when the upregulation of PD‐L1 expression is induced under conditions of symmetrically stimulated immune activation. ATR, ataxia telangiectasia and Rad3 related; cGAS, cyclic GMP‐AMP synthase; Chk1, checkpoint kinase 1; DAMP, damage‐associated molecular pattern; DC, dendritic cell; HLA, human leukocyte antigen; IFN, interferon; IRF, interferon regulatory factor; STING, stimulator of interferon genes