ALDH1A3 as a Novel Therapeutic Target in Mesothelioma: impact of its inhibition on tumour growth and neutrophil recruitment

Malignant pleural mesothelioma (MPM) is a rare and an aggressive cancer that develops in the protective lining around the lungs, caused by asbestos exposure. Despite widespread knowledge of the hazards of asbestos exposure and its ban in different countries, it has been recently estimated that >20 million people worldwide are at risk to develop it, due to the continuing use around the world and environmental pollution. The high number of MPM patients who do not respond to first-line chemotherapy (Cisplatin/Pemetrexed), as well as increased second-line therapies failure, suggest exploring novel mechanism-based therapies. In absence of strategic oncogenic drivers to stratify MPM patients, it is crucial to identify signaling pathways that drive MPM development and sustain its maintenance. Recently, FDA and EMA approved two immunotherapy agents as a frontline treatment option in unresectable MPMs, despite promising clinical results, mechanisms governing primary and secondary immunecheckpoint blockers resistance remain to be elucidated. Analysis of 84 MPM patients from the TGCA database revealed that high Aldehyde Dehydrogenase 1A3 (ALDH1A3) expression is significantly associated with worse prognosis. The ALDH1A subfamily of 19 isoenzymes, comprised of isoforms ALDH1A1, ALDH1A2, and ALDH1A3, irreversibly convert retinaldehyde to retinoic acid, and is critical for detoxification of endogenous and exogenous aldehyde substrates to their corresponding carboxylic acids. Previous clinical studies highlighted the high expression of ALDH1A3 in cancer stem cells (CSCs) correlated to a higher risk of cancer relapses, drug resistance and a poor clinical outcome. All these evidence led us to engage ALDH1A3 as therapeutic target in MPM. The objective of this study is a comprehensive understanding of the role of ALDH1A3 and the impact of its inhibition in MPM progression and tumor microenvironment, with a deep characterization of the neutrophil compartment.