1. Sculpting the tumour microenvironment by combining radiotherapy and ATR inhibition for curative-intent adjuvant immunotherapy.
- Author
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Patin EC, Nenclares P, Chan Wah Hak C, Dillon MT, Patrikeev A, McLaughlin M, Grove L, Foo S, Soliman H, Barata JP, Marsden J, Baldock H, Gkantalis J, Roulstone V, Kyula J, Burley A, Hubbard L, Pedersen M, Smith SA, Clancy-Thompson E, Melcher AA, Ono M, Rullan A, and Harrington KJ
- Subjects
- Animals, Female, Humans, Mice, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes radiation effects, CD40 Antigens metabolism, CD40 Antigens immunology, CD40 Antigens antagonists & inhibitors, CD8-Positive T-Lymphocytes immunology, Cell Line, Tumor, Head and Neck Neoplasms immunology, Head and Neck Neoplasms therapy, Head and Neck Neoplasms radiotherapy, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Mice, Inbred C57BL, NK Cell Lectin-Like Receptor Subfamily C metabolism, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor metabolism, T-Lymphocytes, Cytotoxic immunology, Ataxia Telangiectasia Mutated Proteins metabolism, Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors, B7-H1 Antigen antagonists & inhibitors, B7-H1 Antigen metabolism, Immunotherapy methods, Squamous Cell Carcinoma of Head and Neck immunology, Squamous Cell Carcinoma of Head and Neck radiotherapy, Squamous Cell Carcinoma of Head and Neck therapy, Squamous Cell Carcinoma of Head and Neck pathology, Tumor Microenvironment radiation effects
- 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., (© 2024. The Author(s).)- Published
- 2024
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