@article {Patine004306, author = {Emmanuel C Patin and Magnus T Dillon and Pablo Nenclares and Lorna Grove and Heba Soliman and Isla Leslie and Davina Northcote and Galabina Bozhanova and Eva Crespo-Rodriguez and Holly Baldock and Harriet Whittock and Gabriella Baker and Joan Kyula and Jeane Guevara and Alan A Melcher and James Harper and Hormas Ghadially and Simon Smith and Malin Pedersen and Martin McLaughlin and Kevin J Harrington}, title = {Harnessing radiotherapy-induced NK-cell activity by combining DNA damage{\textendash}response inhibition and immune checkpoint blockade}, volume = {10}, number = {3}, elocation-id = {e004306}, year = {2022}, doi = {10.1136/jitc-2021-004306}, publisher = {BMJ Specialist Journals}, abstract = {Background Despite therapeutic gains from immune checkpoint inhibitors (ICI) in many tumor types, new strategies are needed to extend treatment benefits, especially in patients failing to mount effective antitumor T-cell responses. Radiation and drug therapies can profoundly affect the tumor immune microenvironment. Here, we aimed to identify immunotherapies to increase the antitumor response conferred by combined ataxia telangiectasia and Rad3-related kinase inhibition and radiotherapy.Methods Using the human papillomavirus (HPV)-negative murine oral squamous cell carcinoma model, MOC2, we assessed the nature of the antitumor response following ataxia telangiectasia and Rad3-related inhibitor (ATRi)/radiotherapy (RT) by performing RNA sequencing and detailed flow cytometry analyses in tumors. The benefit of immunotherapies based on T cell immunoreceptor with Ig and ITIM domains (TIGIT) and Programmed cell death protein 1 (PD-1) immune checkpoint blockade following ATRi/RT treatment was assessed in the MOC2 model and confirmed in another HPV-negative murine oral squamous cell carcinoma model called SCC7. Finally, immune profiling was performed by flow cytometry on blood samples in patients with head and neck squamous cell carcinoma enrolled in the PATRIOT clinical trial of combined ATRi/RT.Results ATRi enhances radiotherapy-induced inflammation in the tumor microenvironment, with natural killer (NK) cells playing a central role in maximizing treatment efficacy. We demonstrated that antitumor activity of NK cells can be further boosted with ICI targeting TIGIT and PD-1. Analyses of clinical samples from patients receiving ATRi (ceralasertib) confirm the translational potential of our preclinical studies.Conclusion This work delineates a previously unrecognized role for NK cells in the antitumor immune response to radiotherapy that can be augmented by small-molecule DNA damage{\textendash}response inhibitors and immune checkpoint blockade.Data are available upon reasonable request.}, URL = {https://jitc.bmj.com/content/10/3/e004306}, eprint = {https://jitc.bmj.com/content/10/3/e004306.full.pdf}, journal = {Journal for ImmunoTherapy of Cancer} }