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

Autor: Patin EC; Targeted Therapy Team, The Institute of Cancer Research, London, UK. emmanuel.patin@icr.ac.uk., Nenclares P; Targeted Therapy Team, The Institute of Cancer Research, London, UK.; The Royal Marsden Hospital, London, UK., Chan Wah Hak C; Targeted Therapy Team, The Institute of Cancer Research, London, UK.; The Royal Marsden Hospital, London, UK., Dillon MT; Targeted Therapy Team, The Institute of Cancer Research, London, UK.; The Royal Marsden Hospital, London, UK., Patrikeev A; Targeted Therapy Team, The Institute of Cancer Research, London, UK., McLaughlin M; Targeted Therapy Team, The Institute of Cancer Research, London, UK., Grove L; Targeted Therapy Team, The Institute of Cancer Research, London, UK.; The Royal Marsden Hospital, London, UK., Foo S; Targeted Therapy Team, The Institute of Cancer Research, London, UK., Soliman H; The Royal Marsden Hospital, London, UK., Barata JP; The Royal Marsden Hospital, London, UK., Marsden J; The Royal Marsden Hospital, London, UK., Baldock H; Targeted Therapy Team, The Institute of Cancer Research, London, UK., Gkantalis J; Targeted Therapy Team, The Institute of Cancer Research, London, UK., Roulstone V; Targeted Therapy Team, The Institute of Cancer Research, London, UK., Kyula J; Targeted Therapy Team, The Institute of Cancer Research, London, UK., Burley A; Targeted Therapy Team, The Institute of Cancer Research, London, UK., Hubbard L; Targeted Therapy Team, The Institute of Cancer Research, London, UK., Pedersen M; Targeted Therapy Team, The Institute of Cancer Research, London, UK., Smith SA; Early Oncology R&D, AstraZeneca, Cambridge, UK., Clancy-Thompson E; Early Oncology R&D, AstraZeneca, Cambridge, UK., Melcher AA; Translational Immunotherapy Team, The Institute of Cancer Research, London, UK., Ono M; Department of Life Sciences, Imperial College London, London, UK., Rullan A; Targeted Therapy Team, The Institute of Cancer Research, London, UK.; The Royal Marsden Hospital, London, UK., Harrington KJ; Targeted Therapy Team, The Institute of Cancer Research, London, UK.; The Royal Marsden Hospital, London, UK.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 13; Vol. 15 (1), pp. 6923. Date of Electronic Publication: 2024 Aug 13.
DOI: 10.1038/s41467-024-51236-6
Abstrakt: 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).)
Databáze: MEDLINE
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