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ARTICLE

Investigating the Immune Effects of Radiotherapy in Non-Small Cell Lung Cancer—Results of the PD-RAD Study

Shuhui Cheng1, Tiana Kordbacheh1, Antonia Banyard2, Anshuman Chaturvedi3, Diego Sanchez Martinez2, Crispin T. Hiley4,5, Maggie Harris3, Clara Chan3, Corinne Faivre-Finn3, Timothy M. Illidge1,3,#, Eleanor J. Cheadle1,#,*
1 Targeted Therapy Group, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M20 4BX, UK
2 Cancer Research UK Manchester Institute, The University of Manchester, Manchester, M20 4BX, UK
3 The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
4 University College London Hospitals NHS Foundation Trust, London, WC1E 6AG, UK
5 Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, WC1E 6BT, UK
* Corresponding Author: Eleanor J. Cheadle. Email: email
# These authors contributed equally
(This article belongs to the Special Issue: Tumor Biomarkers for Diagnosis, Prognosis and Targeted Therapy)

Oncology Research https://doi.org/10.32604/or.2025.072053

Received 18 August 2025; Accepted 31 December 2025; Published online 20 January 2026

Abstract

Objectives: The PACIFIC trial established the benefit of durvalumab following chemo-radiotherapy for stage III non-small cell lung cancer (NSCLC). However, the concurrent use of radiotherapy (RT) and durvalumab (PACIFIC-2 trial) showed no additional advantage. The PD-RAD study was set up to understand the immunological effects of RT on the tumor microenvironment (TME) to aid in optimizing sequencing of combination therapies. Methods: The PD-RAD trial (ClinicalTrials.gov identifier: NCT03258788) aimed to enroll thirty NSCLC patients receiving radical-intent RT. Tumor biopsies and blood samples were collected pre-RT and at week 2 during RT and analyzed using multiplex immunohistochemistry (mIHC) and high-dimensional mass cytometry (CyTOF), respectively. Results: Paired biopsies were collected from only three patients (Pts 1, 3 & 4) and blood from four patients (Pts 1–4) before the study was closed early during the COVID-19 pandemic. Programmed Death-Ligand 1 (PD-L1) expression in the TME was raised in Patient 1, who responded well to treatment, and unaltered in two patients with progressive disease. CyTOF analysis revealed elevated circulating classical monocytes, highest in the patient with a good response. Conclusions: This study underscores the challenges of integrating advanced immune monitoring during RT delivery and did not meet its primary endpoint. The hypothesis-generating findings highlight PD-L1+ macrophages in the TME and classical monocytes in the blood as potential immune biomarkers of RT response, but larger studies are needed to validate these observations and characterize the immune changes following curative-intent RT in patients with NSCLC.

Keywords

Non-small cell lung cancer (NSCLC); radiotherapy; tumor microenvironment; biomarker; programmed death-ligand 1 (PD-L1); classical monocytes

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