Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer?

SIMPLE SUMMARY: Immunotherapies have revolutionized the management of advanced stage cancer; however, not all patients benefit given many cancers are resistant to immune checkpoint inhibitors. To support rapid growth, malignant cells frequently bypass the cell cycle checkpoints that normally ensure high-fidelity DNA replication prior to cell division. Therefore, cancer cells (lacking early cell cycle checkpoints) are under high replication stress and rely more heavily on the DNA damage response (DDR) for survival and growth. DDR pathways are long-recognized anti-neoplastic targets. Recently, preclinical studies have demonstrated unexpected crosstalk between these pathways and the immune system. Here, we discuss emerging evidence linking cell cycle biology and the DDR to innate and adaptive immunity. We present a rationale for why Merkel cell carcinoma could serve as a paradigm for studying DDR inhibitors as novel agents to overcome resistance to programmed cell death-1 (PD-1) pathway blockade. ABSTRACT: Metastatic cancers resistant to immunotherapy require novel management strategies. DNA damage response (DDR) proteins, including ATR (ataxia telangiectasia and Rad3-related), ATM (ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase), have been promising therapeutic targets for decades. Specific, potent DDR inhibitors (DDRi) recently entered clinical trials. Surprisingly, preclinical studies have now indicated that DDRi may stimulate anti-tumor immunity to augment immunotherapy. The mechanisms governing how DDRi could promote anti-tumor immunity are not well understood; however, early evidence suggests that they can potentiate immunogenic cell death to recruit and activate antigen-presenting cells to prime an adaptive immune response. Merkel cell carcinoma (MCC) is well suited to test these concepts. It is inherently immunogenic as ~50% of patients with advanced MCC persistently benefit from immunotherapy, making MCC one of the most responsive solid tumors. As is typical of neuroendocrine cancers, dysfunction of p53 and Rb with upregulation of Myc leads to the very rapid growth of MCC. This suggests high replication stress and susceptibility to DDRi and DNA-damaging agents. Indeed, MCC tumors are particularly radiosensitive. Given its inherent immunogenicity, cell cycle checkpoint deficiencies and sensitivity to DNA damage, MCC may be ideal for testing whether targeting the intersection of the DDR checkpoint and the immune checkpoint could help patients with immunotherapy-refractory cancers.