Multimodal characterisation of the longitudinal radiation-induced changes in the immune landscape of primary breast cancers
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Embargo End Date
2026-06-08
ICR Authors
Authors
Yoneyama, M
Document Type
Thesis or Dissertation
Date
2025-12-08
Date Accepted
Abstract
Despite ongoing interest in combining radiotherapy (RT) with immunotherapy in breast cancer
management, there is a lack of understanding of the e=ect of RT alone on the in situ tumour
microenvironment (TME) and anti-tumour immune response. Utilising a unique dataset of clinical
samples from the PRADA and Neo-RT trials, which tested neoadjuvant RT (NART) in primary breast
cancer patients, this thesis sought to characterise longitudinal in situ and systemic immunoradiobiological
changes.
Assessment of stromal tumour-infiltrating lymphocytes (sTILs) using both manual and deep learningbased
methods suggested that NART contributes to a significant and long-term loss of lymphocytes
from the TME, mirrored by systemic lymphodepletion. However, associations between sTILs and
patient outcomes suggested complex underlying immune biology within the irradiated TME. To further
understand the phenotypic composition and spatial distribution of these sTILs, two multiplex
immunofluorescence panels were applied and revealed significant enrichment of Granzyme B+ cells
among sTILs following NART, as well as di=erences in changes to CD20+ B-cell and FoxP3+ Treg
representation between responders and non-responders during NART. On-treatment enrichment of
immune hotspot-related cellular neighbourhoods within the TME also associated with better response
to treatment. In parallel, characterisation of the T-cell receptor (TCR) repertoire showed that early
NART-induced changes to clustering and clonotype abundance in the tumour associated with better
response.
Altogether this thesis presents novel experimental data to address the existing knowledge gap of how
RT itself a=ects the in situ breast TME, at clinically pertinent RT dose-fractionations, and importantly
suggests that longitudinal radiation-induced immune dynamics may associate with eventual
response to treatment. This work thus contributes valuable insights to the ongoing discussion of how
the immunomodulatory e=ects of RT can be optimally and rationally used for synergistic
combinations with immunomodulatory agents, in this new era of breast cancer immunotherapy.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Trans Breast Radiobiol