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

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.

Therapeutic Targeting of DNA Damage Response in Cancer

“…Other DDR inhibitors are also undergoing active clinical investigations in combination with immune checkpoint inhibitors. As these two classes of drugs may show synergistic effects by targeting different tumor vulnerabilities, future trial results are anticipated to provide a broader view of therapeutic options [181].…”

Selinexor is a novel inhibitor of DNA damage response in Merkel cell carcinoma

“…To achieve rapid proliferation and growth, MCC depends on the DDR pathway to compensate for the dysfunction of p53 and Rb 1 . In MCPyV‐positive MCC, LT antigens activate both ATR and ATM through the C‐terminal region, whereas sT activates ATM through phosphoregulation 3,7,8 .…”

“…In 2008, a virus called Merkel cell polyomavirus (MCPyV) was identified in ~80% of cases in the USA, connecting MCPyV as the only known human polyomavirus to be associated with a cutaneous carcinoma 2 . Immune checkpoint inhibitors (ICIs), such as programmed death ligand (PD‐L)1 inhibitors, are a successful treatment in ~50% of patients with metastatic MCC 1 …”

“…Goff et al 1 . suggested that inhibition of the DNA damage response (DDR) may be beneficial in patients with metastatic MCC refractory to ICIs.…”

Function and Molecular Mechanism of the DNA Damage Response in Immunity and Cancer Immunotherapy

“…The DDR shapes how the innate immune system responds to tumors, as well as how the adaptive immune system is recruited to sites of malignancy. Consequently, the interconnections of the DDR and the immune system, which maintain genomic fitness and pathogen protection, can be utilized to improve cancer therapeutic strategies ( 5 , 135 , 287 – 291 ). Yet, defining how the DDR impacts immune responses has remained challenging as immune activation can evidently be triggered by different types of DDR components including DNA damage sensors, transducers, and effectors ( 292 ).…”