Sculpting the tumour microenvironment by combining radiotherapy and ATR inhibition for curative-intent adjuvant immunotherapy

Emmanuel C. Patin (), Pablo Nenclares, Charleen Chan Wah Hak, Magnus T. Dillon, Anton Patrikeev, Martin McLaughlin, Lorna Grove, Shane Foo, Heba Soliman, Joao P. Barata, Joanna Marsden, Holly Baldock, Jim Gkantalis, Victoria Roulstone, Joan Kyula, Amy Burley, Lisa Hubbard, Malin Pedersen, Simon A. Smith, Eleanor Clancy-Thompson, Alan A. Melcher, Masahiro Ono, Antonio Rullan and Kevin J. Harrington
Additional contact information
Emmanuel C. Patin: The Institute of Cancer Research
Pablo Nenclares: The Institute of Cancer Research
Charleen Chan Wah Hak: The Institute of Cancer Research
Magnus T. Dillon: The Institute of Cancer Research
Anton Patrikeev: The Institute of Cancer Research
Martin McLaughlin: The Institute of Cancer Research
Lorna Grove: The Institute of Cancer Research
Shane Foo: The Institute of Cancer Research
Heba Soliman: The Royal Marsden Hospital
Joao P. Barata: The Royal Marsden Hospital
Joanna Marsden: The Royal Marsden Hospital
Holly Baldock: The Institute of Cancer Research
Jim Gkantalis: The Institute of Cancer Research
Victoria Roulstone: The Institute of Cancer Research
Joan Kyula: The Institute of Cancer Research
Amy Burley: The Institute of Cancer Research
Lisa Hubbard: The Institute of Cancer Research
Malin Pedersen: The Institute of Cancer Research
Simon A. Smith: AstraZeneca
Eleanor Clancy-Thompson: AstraZeneca
Alan A. Melcher: The Institute of Cancer Research
Masahiro Ono: Imperial College London
Antonio Rullan: The Institute of Cancer Research
Kevin J. Harrington: The Institute of Cancer Research

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract The combination of radiotherapy/chemoradiotherapy and immune checkpoint blockade can result in poor outcomes in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Here, we show that combining ATR inhibition (ATRi) with radiotherapy (RT) increases the frequency of activated NKG2A+PD-1+ T cells in animal models of HNSCC. Compared with the ATRi/RT treatment regimen alone, the addition of simultaneous NKG2A and PD-L1 blockade to ATRi/RT, in the adjuvant, post-radiotherapy setting induces a robust antitumour response driven by higher infiltration and activation of cytotoxic T cells in the tumour microenvironment. The efficacy of this combination relies on CD40/CD40L costimulation and infiltration of activated, proliferating memory CD8+ and CD4+ T cells with persistent or new T cell receptor (TCR) signalling, respectively. We also observe increased richness in the TCR repertoire and emergence of numerous and large TCR clonotypes that cluster based on antigen specificity in response to NKG2A/PD-L1/ATRi/RT. Collectively, our data point towards potential combination approaches for the treatment of HNSCC.

Date: 2024
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DOI: 10.1038/s41467-024-51236-6

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