ESTRO 2025 - Abstract Book

S72

Invited Speaker

ESTRO 2025

Abstract:

The metabolic landscape of established solid cancers contributes to a hostile micro-environment for tumour infiltrating immune cells. The constant proliferative demand of cancer cells depletes essential nutrients, generates toxic metabolic waste products, and contributes to tumour acidification and hypoxia, which are associated with resistance to both radiotherapy and immunotherapy. Our lab is currently developing methodologies to determine the immunometabolic profile of tumour-infiltrating immune cells. As a complement to conventional methods of determining cellular metabolism in bulk cell populations (e.g. seahorse assay), the flow cytometry-based SCENITH method allows for measuring metabolic dependencies of multiple immune populations at the single cell level simultaneously. Using this method, together with additional imaging-based assessments of mitochondrial dependencies, we are establishing the immunometabolic determinants of radiotherapy response in mice. Further, the essential metabolites for cellular energy conversion, ATP and NAD+, become powerful immunogenic signals when released into the extracellular space and they play central roles in maintaining tissue immune homeostasis. However, in the tumour microenvironment, cancer cells can take advantage of these nucleotides by converting them into immunosuppressive metabolites or by using them as substrates for directly killing tumour infiltrating lymphocytes. Our preclinical studies indicate that ART1, a tumour-expressed mono-ADP ribosyltransferase, may be a central player in radiation-induced immune modulation. ART1 uses free NAD+ to ADP ribosylate the P2X7R receptor on tumour-infiltrating immune cells, resulting in their elimination through NAD induced cell death (NICD). In lung tumour-bearing mice treated with radiotherapy (8Gyx3) directed to one lung, ART1-blockade alone, or in combination with immune checkpoint blockade, fundamentally shifted the tumour immune landscape in both irradiated and non-irradiated lungs, promoting activation of conventional type I dendritic cells and CD8 tissue resident memory T cells. Further, in flank tumour models of lung cancer and head and neck cancer, ART1-blockade in combination with hypofractionated radiotherapy delayed tumour growth and extended survival compared with radiotherapy or ART1 blockade alone. In summary, radiotherapy may have a significant impact on the immunometabolic profile of tumour-infiltrating lymphocytes and is a field of research that needs further exploration. Tumour-expressed radiation-induced checkpoints can offset the immunogenic response to radiotherapy and targeting of these checkpoints could improve the efficacy of radiotherapy-immunotherapy combinations. Speaker Abstracts Breast-conserving therapy or mastectomy among patients with or without the BRCA1/2 variant: The breast surgeon point of view Isabel T. Rubio Breast Surgical Oncology Unit, Clinica Universidad de Navarra, Madrid, Spain. Breast Cancer Center, Cancer Center Clinica Universidad de Navarra, Madrid, Spain Abstract: Breast cancer surgery has become complex in the last decade. Nowadays, the surgical options, when a cancer diagnosis is made, needs to take into account genetic factors, risk factors, adjuvant treatments, tumor and patient characteristics, as well as patient preferences. The surgical options aim to minimize the morbidity, maximize oncological and cosmetic outcomes and improve patient´s quality of life. 4762