S2540
Radiobiology – Immuno-radiobiology
ESTRO 2026
Keywords: Low-dose radiotherapy; SBRT; immunotherapy
Proffered Paper 4148
SBRT embedded in low-dose RT plus αPD-1 against bulky tumors via an IFN-I/NK/DC/CD8+ T cell axis Ren Luo, Yu Min, Kai Kang, Yufeng Zhang, Shanghai Liu, Jianxin Xue, You Lu Thoracic Oncology Ward, West China Hospital, Chengdu, China Purpose/Objective: Bulky tumors remain difficult to treat. Stereotactic body radiation therapy (SBRT) induces immunogenic cell death and activates T-cell–mediated antitumor immunity, whereas low-dose radiation (LDRT) remodels the tumor microenvironment (TME) by recruiting immune cells. We developed a novel radiotherapy technique, EclipseRT (ERT), which delivers SBRT to tumor subvolume(s) while applying LDRT to the entire tumor, creating an “eclipse”-like dose distribution. This study evaluated the safety and efficacy of ERT to bulky lesions with PD-1 inhibitors (iERT)in mice and patients. Material/Methods: In mice bearing CT26 colon, LLC1 lung, and B16-OVA melanoma bulky tumors, the entire tumor received LDRT (2 Gy × 3), while SBRT (10 Gy × 3) targeted the center; α PD-1 was administered weekly. The roles of CD8 ⁺ T and NK cells in mediating therapeutic effects were assessed using depleting antibodies. Immune cell dynamics were assessed by flow cytometry, and scRNA-seq was performed to profile the TME after iERT. Patients with advanced lung or liver bulky tumors who failed standard treatment or with oncologic emergencies were treated. Results: iERT achieved superior tumor control compared with SBRT/ α PD-1 or LDRT/ α PD-1 across all three models. In CT26 tumors, iERT induced complete regression in 3 of 11 mice and increased tumor-specific CD8 ⁺ T cells within the TME. Its efficacy depended on both CD8 ⁺ T cells and NK cells. scRNA-seq and validation experiments revealed that SBRT robustly induced type I interferon signaling, activating NK cells to secrete XCL1 and recruit cross-presenting XCR1 ⁺ DCs. LDRT further enhanced NK and CD8 ⁺ T-cell infiltration. Thirty-nine patients with advanced cancer received iERT. Among 26 thoracic cases, one developed radiation pneumonitis. No grade ≥ III toxicity occurred. The objective response rate was 38.5%, with median progression-free and overall survival of 5.6 and 23.0 months, respectively. Conclusion: Collectively, iERT activates the IFN-I/NK/DC/CD8 ⁺ T-cell axis, inducing viral mimicry and robust antitumor immunity against bulky tumors. This strategy was safe and effective in patients, warranting further clinical evaluation.
Proffered Paper 4500 Neo-adjuvant radiotherapy alters the
transcriptomic and topographical immune landscape of tumour-draining lymph nodes in breast cancer patients Matthew Fenton 1,2 , Miki Yoneyama 1 , Selvakumar Anbalagan 1 , Adrian Larkeryd 3 , Emma Westlund 4 , Beatriz Monterde Martinez 3 , Luis Zapata Ortiz 3 , Charlotte E Coles 5 , Alan Melcher 1 , Anita Grigoriadis 6 , Ioannis Roxanis 1 , Tom Lund 3 , Navita Somaiah 1,2 1 Division of Radiotherapy and Imaging, Institute of Cancer Research, London, United Kingdom. 2 Breast Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom. 3 Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom. 4 Light Microscopy Facility Sutton, Institute of Cancer Research, London, United Kingdom. 5 Department of Oncology, University of Cambridge, Cambridge, United Kingdom. 6 Cancer Bioinformatics, School of Cancer & Pharmaceutical Sciences, Kings College London, London, United Kingdom Purpose/Objective: In breast cancer, adjuvant radiotherapy to tumour- draining lymph nodes (TDLNs) improves locoregional control. Conversely, TDLN irradiation can prevent robust pre-clinical anti-tumour immune responses to radiotherapy +/- immunotherapy, by impairing tumour-specific CD8 T-cell activation in TDLNs and their infiltration into the primary tumour1-3. However, there is a paucity of data regarding the immune impacts of radiotherapy on human TDLNs in breast cancer. Therefore, we are performing multimodal analysis of pre-/post-radiotherapy TDLNs from unique neo-adjuvant breast radiotherapy trial datasets (PRADA4; NCT02771938 and Neo-RT5; NCT03818100). Material/Methods: Before surgery, PRADA patients (n=32) received chemotherapy then radiotherapy (40.05Gy/15 fractions/3 weeks; 87.5% including TDLN regions). Neo-RT patients (n=13) received radiotherapy then endocrine therapy. Post-treatment PRADA TDLNs were excised ~3 weeks post-radiotherapy.12 baseline and 39 post-radiotherapy TDLN FFPE blocks (paired from 1 Neo-RT and 8 PRADA patients) were stained using 6- plex immunofluorescence lymphoid panel, imaged on the Akoya Biosciences PhenoImager HT, and analysed using QuPath (v0.5.1). RNA was extracted and sequenced using an exome-capture method. 8 baseline and 14 post-radiotherapy TDLN blocks (from above patients) were included for analysis, performed using DESeq2 and immunedeconv/CIBERSORTx.
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