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

Nat Commun. 2024 Aug 13;15(1):6923. doi: 10.1038/s41467-024-51236-6.

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.

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins* / antagonists & inhibitors
  • Ataxia Telangiectasia Mutated Proteins* / metabolism
  • B7-H1 Antigen* / antagonists & inhibitors
  • B7-H1 Antigen* / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / radiation effects
  • CD40 Antigens / antagonists & inhibitors
  • CD40 Antigens / immunology
  • CD40 Antigens / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Female
  • Head and Neck Neoplasms / immunology
  • Head and Neck Neoplasms / radiotherapy
  • Head and Neck Neoplasms / therapy
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunotherapy* / methods
  • Mice
  • Mice, Inbred C57BL
  • NK Cell Lectin-Like Receptor Subfamily C / metabolism
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / metabolism
  • Squamous Cell Carcinoma of Head and Neck* / immunology
  • Squamous Cell Carcinoma of Head and Neck* / pathology
  • Squamous Cell Carcinoma of Head and Neck* / radiotherapy
  • Squamous Cell Carcinoma of Head and Neck* / therapy
  • T-Lymphocytes, Cytotoxic / immunology
  • Tumor Microenvironment* / radiation effects

Substances

  • Ataxia Telangiectasia Mutated Proteins
  • ATR protein, human
  • B7-H1 Antigen
  • CD40 Antigens
  • Immune Checkpoint Inhibitors
  • NK Cell Lectin-Like Receptor Subfamily C
  • Programmed Cell Death 1 Receptor