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Review

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

1
Department of Radiation Oncology, University of Washington, Seattle, WA 98195, USA
2
Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA 98109, USA
3
Institute for Stem Cell and Regenerative Medicine, Department of Bioengineering, University of Washington, Seattle, WA 98109, USA
4
Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA 98109, USA
5
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to the work.
Academic Editor: Kavita Y. Sarin
Cancers 2021, 13(14), 3415; https://doi.org/10.3390/cancers13143415
Received: 9 June 2021 / Revised: 4 July 2021 / Accepted: 5 July 2021 / Published: 8 July 2021
(This article belongs to the Special Issue Molecular Mechanisms of Skin Cancer)
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.
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. View Full-Text
Keywords: immune checkpoint inhibitors; ATR; ATM; DNA-PK; DNA damage response inhibitors; Merkel cell carcinoma; PD-1 pathway; cell cycle checkpoint; immunogenic cell death immune checkpoint inhibitors; ATR; ATM; DNA-PK; DNA damage response inhibitors; Merkel cell carcinoma; PD-1 pathway; cell cycle checkpoint; immunogenic cell death
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MDPI and ACS Style

Goff, P.H.; Bhakuni, R.; Pulliam, T.; Lee, J.H.; Hall, E.T.; Nghiem, P. Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer? Cancers 2021, 13, 3415. https://doi.org/10.3390/cancers13143415

AMA Style

Goff PH, Bhakuni R, Pulliam T, Lee JH, Hall ET, Nghiem P. Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer? Cancers. 2021; 13(14):3415. https://doi.org/10.3390/cancers13143415

Chicago/Turabian Style

Goff, Peter H., Rashmi Bhakuni, Thomas Pulliam, Jung H. Lee, Evan T. Hall, and Paul Nghiem. 2021. "Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer?" Cancers 13, no. 14: 3415. https://doi.org/10.3390/cancers13143415

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