Longitudinal assessment of tumor-infiltrating lymphocytes in primary breast cancer following neoadjuvant radiotherapy

Miki Yoneyama; Konstantinos Zormpas-Petridis; Ruth Robinson; Faranak Sobhani; Elena Provenzano; Harriet Steel; Sara Lightowlers; Catherine Towns; Simon P Castillo; Selvakumar Anbalagan; Tom Lund; Erik Wennerberg; Alan Melcher; Charlotte E Coles; Ioannis Roxanis; Yinyin Yuan; Navita Somaiah

doi:10.1016/j.ijrobp.2024.04.065

Longitudinal assessment of tumor-infiltrating lymphocytes in primary breast cancer following neoadjuvant radiotherapy

Int J Radiat Oncol Biol Phys. 2024 Apr 26:S0360-3016(24)00566-2. doi: 10.1016/j.ijrobp.2024.04.065. Online ahead of print.

Authors

Miki Yoneyama¹, Konstantinos Zormpas-Petridis², Ruth Robinson³, Faranak Sobhani⁴, Elena Provenzano⁵, Harriet Steel¹, Sara Lightowlers⁶, Catherine Towns⁷, Simon P Castillo⁴, Selvakumar Anbalagan¹, Tom Lund⁸, Erik Wennerberg¹, Alan Melcher¹, Charlotte E Coles⁶, Ioannis Roxanis⁹, Yinyin Yuan¹⁰, Navita Somaiah¹¹

Affiliations

¹ Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.
² Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK; Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
³ Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK.
⁴ Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
⁵ Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁶ Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Department of Oncology, University of Cambridge, Cambridge, UK.
⁷ Department of Oncology, University of Cambridge, Cambridge, UK.
⁸ Integrated Pathology Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK.
⁹ The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
¹⁰ Division of Molecular Pathology, The Institute of Cancer Research, London, UK. Electronic address: YYuan6@mdanderson.org.
¹¹ Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK. Electronic address: navita.somaiah@icr.ac.uk.

PMID: 38677525
DOI: 10.1016/j.ijrobp.2024.04.065

Abstract

Background: Tumor-infiltrating lymphocytes (TILs) have prognostic significance in several cancers, including breast. Despite interest in combining radiotherapy with immunotherapy, little is known about the effect of radiotherapy itself on the tumor-immune microenvironment, including TILs. Here, we interrogated longitudinal dynamics of tumor-infiltrating and systemic lymphocytes in patient samples taken before, during, and after neoadjuvant radiotherapy (NART), from XXX and XXX breast clinical trials.

Methods: We manually scored stromal TILs (sTILs) from longitudinal tumor samples using standardized guidelines, as well as deep learning-based scores at cell-level (cTIL) and cell- and tissue-level combination analysis (SuperTIL). In parallel, we interrogated absolute lymphocyte counts from routine blood tests at corresponding timepoints during treatment. Exploratory analyses studied the relationship between TILs and pathological complete response (pCR) and long-term outcomes.

Results: Patients receiving NART experienced a significant and uniform decrease in sTILs that did not recover at the time of surgery (P < 0.0001). This lymphodepletive effect was also mirrored in peripheral blood. Our "SuperTIL" deep learning score showed good concordance with manual sTILs, and importantly performed comparably to manual scores in predicting pCR from diagnostic biopsies. Analysis suggested an association between baseline sTILs and pCR, as well as sTILs at surgery and relapse, in patients receiving NART.

Conclusions: This study provides novel insights into TIL dynamics in the context of NART in breast cancer, and demonstrates the potential for artificial intelligence to assist routine pathology. We have identified trends which warrant further interrogation and have a bearing on future radio-immunotherapy trials.

Keywords: Digital pathology; Tumor-infiltrating lymphocytes; breast cancer; immune-radiobiology; neoadjuvant radiotherapy; tumor-immune microenvironment.