Radiation-induced and obesity dependent NK cell activities against metastatic breast cancer cells

Theoretical framework: Radiation therapy (RT) is one of the leading therapeutic approaches used in the management of metastatic breast cancer (BC). However, currently existing RT schedules are limited in their efficacy due to the impossibility to reach a curative radiation dose for killing of aggressive and radiation resistant carcinoma cells. Although high-LET irradiation could more efficiently eradicate therapy resistant carcinoma cells in comparison with photon-based RT, it is unclear whether it could also better mobilize immune cells for elimination of undifferentiated and radioresistant cancer stem cells (CSCs). Currently, overweight and obesity is an increasing problem that can diminish an efficacy of RT and alter immune response in patients with metastatic BC. Unfortunately, it is still unknown how adipocytes can contribute to the crosstalk between carcinoma and immune cells upon low- and high-LET radiation exposure.

Research objectives: elucidation of the role of obese microenvironment in the regulation of cytotoxic activities of low- and high-LET ionizing radiations and NK cells against BC cells with enhanced metastatic properties.       

Methods: Low- and high-LET irradiation of luminal A and B BC cells with different invasive and migratory abilities, and NK cells in presence or absence of adipocytes obtained from pre-, menopausal, and postmenopausal women with different BMIs, will be used to determine adipocyte-dependent differences in radiation responses, alterations in pro-metastatic properties, and modulation of metabolic activities of the investigated BC cells.

Level of originality and innovation: of the research project consists in an integrated approach of the evaluation of the crosstalk between metastatically-active luminal A BC and NK cells upon photon, proton, and carbon ion irradiation and obese circumstances. There are no reports on adipocyte responses to these kinds of irradiation. It is also unknown whether radiation response and susceptibility to NK lysis of BC cells with enhanced invasive and metastatic capacities can be affected by adipocytes during cell exposure to different kinds of irradiation. Pre-clinical data received during conducting of this project, can be translated into the clinical practice for the development of NK cell-based treatment approaches and novel targeted therapeutics modulating an influence of adipose tissues in luminal BC patients in the context of radiotherapy.   

Primary researchers involved: This is a joint project involving the researchers with different expertises: PI Ira Skvortsova (Austria) and her team (EXTRO-Lab members, Medical University of Innsbruck, Austria); collaborators: Christian Ploner (Medical University of Innsbruck, Austria), Slavisa Tubin (MedAustron, Wr. Neustadt, Austria); Monica Marchese, Olga Kofanova (IBBL, Luxembourg); Alessandra Bisio and Yari Ciribilli (CIBIO, University of Trento, Italy); Anahid Jewett (UCLA School of Dentistry, Los Angeles, USA).