Main Session
Sep
27
PQA 02 - Pediatric Cancer, Sarcoma and Cutaneous Tumors, Medical Education & Professional Development, and Health Services Research
2350 - Fractionation-Dependent Immune Remodeling and Toxicity following Hypofractionated Radiation in Soft-Tissue Sarcoma
Presenter(s)
Logan Mahoney, MS, BS - University of Calgary, Calgary, AB
L. Mahoney1, K. Hildebrand1, C. Salazar1, A. Singla1, F. Jirik1, J. Kendal2, J. M. Stosky3, and M. Monument1; 1University of Calgary, Calgary, AB, Canada, 2Department of Orthopaedic Surgery, University of California, Los Angeles, Santa Monica, CA, 3McGill University Health Centre, Montreal, QC, Canada
Purpose/Objective(s):
STimulation of interferon genes (STING) pathway activation produces durable responses in a subset of soft-tissue sarcomas (STS), yet resistance and treatment-related toxicity remain major barriers to clinical translation. Radiation therapy (RT) is a potent immunomodulator, but how RT fractionation shapes systemic immune signalling and therapeutic window when combined with STING activation is poorly defined. We evaluated fractionation-dependent immune remodelling and toxicity following hypofractionated RT alone and in combination with STING pathway activation.Materials/Methods:
Two immunocompetent murine STS models sharing oncogenic drivers, commonly known as the KP model (Kras G12D mutation and Trp53 loss), differing by PTEN status (PTEN-intact vs PTEN-deficient), were treated with hypofractionated RT (8 Gyx1, 8 Gyx3, or 6 Gyx5) alone or sequenced RT followed by a cyclic dinucleotide STING agonist administered 24-hrs after completion of RT. Serum cytokines were quantified using multiplex panels at 24 hours, 72 hours, & humane endpoint relative to final RT fraction, with rigorously time-matched untreated controls. Tumour growth and treatment-related toxicity were assessed longitudinally.Results:
RT alone induced distinct fractionation-dependent systemic cytokine profiles. Single-fraction RT (8 Gyx1) produced a transient interferon-associated cytokine response peaking at early timepoints with resolution by endpoint. In contrast, multi-fraction regimens (8 Gyx3 and 6 Gyx5) resulted in sustained elevations of inflammatory and myeloid-associated cytokines. Combination therapy with 8 Gyx3 or 6 Gyx5 followed by STING pathway activation led to marked tumour growth arrest but was associated with severe late local toxicity, including ulceration and skin necrosis, necessitating early euthanasia of all treated animals. Such toxicity was not observed with single-fraction RT alone or prior to combination therapy.Conclusion:
Hypofractionated RT induces fractionation-specific systemic immune remodelling with important implications for combination immunotherapy. While multi-fraction RT schedules can profoundly suppress tumour growth when combined with STING pathway activation, excessive toxicity highlights a narrow therapeutic window. These findings support careful selection of RT fractionation when integrating innate immune agonists and inform the design of safer, biomarker-guided RT–immunotherapy strategies for soft-tissue sarcoma.