Combining (chemo)radiotherapy with immunomodulatory agents in head and neck cancer
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Embargo End Date
2026-05-24
ICR Authors
Authors
Chan Wah Hak, C
Document Type
Thesis or Dissertation
Date
2025-11-24
Date Accepted
Abstract
Despite advances in immuno-oncology, attempts to improve outcomes for patients with locally
advanced, unresectable squamous cell carcinoma of the head and neck (SCCHN) using immune
checkpoint inhibitors alongside standard radiotherapy (RT) and chemoradiotherapy (CRT) have largely
failed. Motivated by these translational setbacks, this thesis employed a reverse translational approach
to investigate the immunological effects of RT and CRT using an immunocompetent murine model of
SCCHN, with particular focus on CD8⁺ T-cell dynamics, antigen engagement, and T-cell receptor (TCR)
clonality.RT alone enhanced local tumour control and increased intratumoural CD8⁺ T-cell infiltration
but also triggered immunosuppressive responses. Nr4a3-Tocky reporter analysis revealed a timedependent
rise in CD8⁺ T-cell antigen engagement, with peak expansion of PD-1hi “persistent-arrested”
subsets at days 7-10 post-RT. Despite their activation, these antigen-engaged T-cells were not
functionally required for tumour control, which was shown to be CD8⁺ T-cell-independent. In contrast,
CRT displayed CD8⁺ T-cell-dependent tumour control, suggesting addition of cisplatin sensitises
tumours to T-cell-mediated killing. Single-cell analysis revealed that CRT, more so than RT, enhanced
CD8⁺ T-cell clonal expansion and enriched for effector-like and progenitor-exhausted phenotypes
versus terminally exhausted. However, these shifts were insufficient to synergise with anti-PD-1
therapy, highlighting persistent immunosuppressive barriers. Addition of the inhibitor of apoptosis
protein (IAP) antagonist xevinapant to CRT, while increasing local tumour cell death, paradoxically
impaired the CRT-induced immunological benefits by diminishing CD8⁺ T-cell cell function and
disrupting key innate and adaptive immune pathways.These findings underscore the necessity of
thoroughly characterising the immunomodulatory effects of standard-of-care treatments such RT and
CRT prior to the integration of immunotherapeutic agents. They further highlight the complexity of
combination treatments and the critical need for mechanistic validation to inform rational and effective
combination strategies
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Trans Immunotherapy