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 C. Hubbard, Malin Pedersen, Simon A. Smith, Eleanor Clancy‐Thompson, Alan Melcher, Masahiro Ono, Antonio Rullan, Kevin J. Harrington
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. Immune checkpoint blockade can result in good outcomes in patients with metastatic head and neck squamous cell carcinoma (HNSCC), but not those with locally advanced disease. Here, the authors demonstrate that the addition of anti-NKG2A and anti-PD-L1 blockade to ATR inhibition and radiotherapy in the adjuvant setting can induce a robust antitumour immune response in mice.