ESTRO 2025 - Abstract Book

S3895

Radiobiology - Microenvironment

ESTRO 2025

References: M. Damaghi, J. West, et al., The harsh microenvironment in early breast cancer selects for a Warburg phenotype. Proc. Natl. Acad. Sci. U. S. A. 118 (2021). Y. Xiao, M. Elmasry, et al., Eco-evolutionary Guided Pathomic Analysis to Predict DCIS Upstaging, bioRxiv (2024)p. 2024.06.23.600274. R. Chalar, N. Khatri, et al., Cancer Cells Sphingolipids Metabolic Plasticity Defines Cell Fitness in Adaptation to Acidic Tumor Microenvironments. bioRxiv .(2024)p. 2024.06.23.600274

2421

Digital Poster Investigating resistance mechanisms in low-dose radiation and combinatorial immunotherapy Katiuska Passelli 1,2,3 , Ana Cristina Guerra de Souza 4,2 , Joao Dos Santos Lourenço 4,2 , Anet Valdes Zayas 1,2,3 , Nadine Fournier 4,2 , Fernanda Herrera 1,3,2 1 Department of Oncology, CHUV, Lausanne, Switzerland. 2 Agora Center for Cancer Research, -, Lausanne, Switzerland. 3 Service of Radiation Oncology, CHUV, Lausanne, Switzerland. 4 Translational Data Science Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland Purpose/Objective: Immune checkpoint blockade (ICB) can produce robust and lasting responses, but its efficacy is often limited to a subset of patients. This challenge is particularly pronounced in patients with "cold" or immune desert tumors, characterized by poor immune cell infiltration and an immunosuppressive tumor microenvironment (TME). Consequently, there is an urgent need for innovative combinatorial therapies capable of sustaining T cell-mediated tumor control and overcoming both innate and adaptive resistance mechanisms. We previously demonstrated that a three-week course of orthogonal radio-combinatorial immunotherapy (RACIM)—comprising low dose radiotherapy (LDRT, 1 Gy to the abdominal cavity), ICB targeting PD-1 and CTLA-4, agonistic CD40 antibody, and metronomic cyclophosphamide—achieved initial tumor control in immunologically cold tumors. However, tumor recurrence occurred in 96% of mice and patients, underscoring the limited impact of LDRT on long-term immunotherapy efficacy. This study aims to investigate the resistance mechanisms to RACIM treatment. Material/Methods: To investigate the immunobiology of tumor recurrence and evolution, we profiled murine tumors at the points of best clinical response and progression in the ID8 ovarian tumor model, using scRNAseq, immunofluorescence, and flow cytometry. Results: At tumor progression, ID8 tumors exhibited a loss of exhausted tumor-infiltrating lymphocytes (TILs) previously associated with RACIM response. Furthermore, RACIM progression was marked by heightened infiltration of immunosuppressive tumor-associated neutrophils (TANs) with loss of expression of type I interferon. During the response phase, we identified a macrophage population with a type I interferon signature, whereas at progression, macrophages expressing high levels of ApoE, Trem2 and complement components predominated. Importantly, targeting tumor-associated macrophages (TAMs) with a CSF1-R inhibitor early in RACIM treatment enhanced therapeutic efficacy, highlighting that modulating the immune landscape may improve outcomes in resistant tumors. Conclusion: These findings reveal the dynamic shifts in immune cell populations in response to RACIM and point to potential targets to counteract resistance mechanisms, offering insights for the development of more effective cancer therapies.