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Published on: February 14, 2025
Harnessing radiotherapy-induced NK-cell activity by combining DNA damage-response inhibition and immune checkpoint
Emmanuel C Patin1, Magnus T Dillon2, Pablo Nenclares2,3
1Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK emmanuel.patin@icr.ac.uk.
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-response inhibitors and immune checkpoint blockade.
Insights
Combining DNA damage response inhibitors with radiation therapy enhances natural killer (NK) cell activity. This approach, along with immune checkpoint blockade targeting TIGIT and PD-1, boosts antitumor responses, offering new strategies for cancer treatment.
Area of Science:
- Immunology
- Oncology
- Radiotherapy
Background:
- Immune checkpoint inhibitors (ICIs) show therapeutic promise but require new strategies for patients with insufficient T-cell responses.
- Radiation and drug therapies significantly impact the tumor immune microenvironment.
- Developing novel immunotherapies is crucial to enhance antitumor responses.
Purpose of the Study:
- To identify immunotherapies that augment antitumor responses when combined with ataxia telangiectasia and Rad3-related kinase inhibition and radiotherapy.
- To investigate the role of natural killer (NK) cells in the combined treatment efficacy.
- To assess the translational potential of preclinical findings in head and neck squamous cell carcinoma patients.
Main Methods:
- Utilized HPV-negative murine oral squamous cell carcinoma models (MOC2 and SCC7).
- Performed RNA sequencing and flow cytometry to analyze tumor immune responses.
- Assessed immunotherapies including TIGIT and PD-1 blockade post-ATRi/radiotherapy.
- Conducted immune profiling on blood samples from patients in the PATRIOT clinical trial.
Main Results:
- Ataxia telangiectasia and Rad3-related inhibitor (ATRi) enhances radiotherapy-induced inflammation, with NK cells being key to efficacy.
- Targeting TIGIT and PD-1 further boosts NK cell-mediated antitumor activity.
- Clinical sample analysis confirmed the translational relevance of ATRi treatment.
Conclusions:
- NK cells play a critical, previously unrecognized role in the antitumor immune response to radiotherapy.
- Small-molecule DNA damage-response inhibitors combined with immune checkpoint blockade can augment this NK cell activity.
- This combination strategy holds potential for improving cancer treatment outcomes.
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