Addition of chemotherapy to radiotherapy promotes progenitor-exhausted CD8+ T-cell clonal dominance in head and neck cancer
7 affiliations
- 1Division of Radiotherapy and Imaging, The Institute of Cancer Research, London SW3 6JB, UK
- 2Institute of Immunity and Transplantation, University College London
- 3Flow Cytometry Facility, The Institute of Cancer Research, London SW3 6JB, UK
- 4Biological Services Unit, The Institute of Cancer Research, London SW3 6JB, UK
- 5Head and Neck Unit, The Royal Marsden Hospital, London, UK
- 6Clinical Trials and Statistics Unit at The Institute of Cancer Research (ICR-CTSU)
- 7Faculty of Natural Sciences, Department of Life Sciences, Imperial College London, UK
Abstract
Concomitant chemoradiotherapy (CRT) is a standard-of-care treatment for unresectable locally advanced head and neck squamous cell carcinoma (LA-SCCHN), but its immune effects, particularly relative to radiotherapy (RT) alone, remain incompletely understood. Using syngeneic murine models, we integrated Nr4a3-Tocky reporter analysis with single-cell transcriptomics and T cell receptor clonotyping to comprehensively profile intratumoural CD8+ T-cell responses following RT and CRT. We show that CRT uniquely drives robust clonal expansion of antigen-engaged CD8+ T-cells and biases differentiation toward progenitor-exhausted (TPEX) states, whereas RT favours terminal exhaustion (TEX). Single-cell analyses further reveal preferential clonal dominance within TPEX populations following CRT. In peripheral blood mononuclear cells from patients treated with CRT, TEX populations predominated early after treatment, followed by delayed expansion of circulating TPEX-like populations at 3 months, suggesting phased recovery of progenitor-like T-cell states. Together, these findings demonstrate that CRT and RT induce distinct CD8+ T-cell differentiation trajectories and clonal architectures, providing insight into treatment-induced immune remodelling in LA-SCCHN.
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BibTeX
@article{hak2026addition,
title = {{Addition of chemotherapy to radiotherapy promotes progenitor-exhausted CD8+ T-cell clonal dominance in head and neck cancer}},
author = {Charleen Chan Wah Hak and Anton Patrikeev and Antonio Rullan and Emmanuel C Patin and Victoria Roulstone and Lisa C Hubbard and Matthew Guelbert and Elizabeth S Appleton and Shane Foo and Isaac Dean and Amy Burley and Joan N Kyula-Currie and Holly Baldock and Jen Y Lee and Pablo Nenclares and Hannah Nanapragasam and Carmen Murano and Malin Pedersen and Maggie Chon U Cheang and Shreerang A Bhide and Masahiro Ono and Kevin J Harrington and Alan A Melcher},
journal = {Cancer immunology research},
year = {2026},
month = oct,
doi = {10.1158/2326-6066.cir-26-0706},
url = {https://doi.org/10.1158/2326-6066.cir-26-0706},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Addition of chemotherapy to radiotherapy promotes progenitor-exhausted CD8+ T-cell clonal dominance in head and neck cancer
AU - Charleen Chan Wah Hak
AU - Anton Patrikeev
AU - Antonio Rullan
AU - Emmanuel C Patin
AU - Victoria Roulstone
AU - Lisa C Hubbard
AU - Matthew Guelbert
AU - Elizabeth S Appleton
AU - Shane Foo
AU - Isaac Dean
AU - Amy Burley
AU - Joan N Kyula-Currie
AU - Holly Baldock
AU - Jen Y Lee
AU - Pablo Nenclares
AU - Hannah Nanapragasam
AU - Carmen Murano
AU - Malin Pedersen
AU - Maggie Chon U Cheang
AU - Shreerang A Bhide
AU - Masahiro Ono
AU - Kevin J Harrington
AU - Alan A Melcher
PY - 2026
DA - 2026/10/12
JO - Cancer immunology research
DO - 10.1158/2326-6066.cir-26-0706
UR - https://doi.org/10.1158/2326-6066.cir-26-0706
AB - Concomitant chemoradiotherapy (CRT) is a standard-of-care treatment for unresectable locally advanced head and neck squamous cell carcinoma (LA-SCCHN), but its immune effects, particularly relative to radiotherapy (RT) alone, remain incompletely understood. Using syngeneic murine models, we integrated Nr4a3-Tocky reporter analysis with single-cell transcriptomics and T cell receptor clonotyping to comprehensively profile intratumoural CD8+ T-cell responses following RT and CRT. We show that CRT uniquely drives robust clonal expansion of antigen-engaged CD8+ T-cells and biases differentiation toward progenitor-exhausted (TPEX) states, whereas RT favours terminal exhaustion (TEX). Single-cell analyses further reveal preferential clonal dominance within TPEX populations following CRT. In peripheral blood mononuclear cells from patients treated with CRT, TEX populations predominated early after treatment, followed by delayed expansion of circulating TPEX-like populations at 3 months, suggesting phased recovery of progenitor-like T-cell states. Together, these findings demonstrate that CRT and RT induce distinct CD8+ T-cell differentiation trajectories and clonal architectures, providing insight into treatment-induced immune remodelling in LA-SCCHN.
SN - 2326-6066
SN - 2326-6074
ER -