Cancer is highly infiltrated by myeloid-derived suppressor cells (MDSCs). Currently available immunotherapies do not completely eradicate MDSCs. Through a genome-wide analysis of the translatome of prostate cancers driven by different genetic alterations, we demonstrate that prostate cancer rewires its secretome at the translational level to recruit MDSCs.
Among different secreted proteins released by prostate tumor cells, we identified Hgf, Spp1 and Bgn as the key factors that regulate MDSC migration. Mechanistically, we found that the coordinated loss of Pdcd4 and activation of the MNK/eIF4E pathways regulate the mRNAs translation of Hgf, Spp1 and Bgn. MDSC infiltration and tumor growth were dampened in prostate cancer treated with the MNK1/2 inhibitor eFT508 and/or the AKT inhibitor ipatasertib, either alone or in combination with a clinically available MDSC-targeting immunotherapy. This work provides a therapeutic strategy that combines translation inhibition with available immunotherapies to restore immune surveillance in prostate cancer.
Nature cancer. 2023 Jul 17 [Epub ahead of print]
Daniela Brina, Adele Ponzoni, Martina Troiani, Bianca Calì, Emiliano Pasquini, Giuseppe Attanasio, Simone Mosole, Michela Mirenda, Mariantonietta D'Ambrosio, Manuel Colucci, Ilaria Guccini, Ajinkya Revandkar, Abdullah Alajati, Toma Tebaldi, Deborah Donzel, Fabio Lauria, Nahjme Parhizgari, Aurora Valdata, Martino Maddalena, Arianna Calcinotto, Marco Bolis, Andrea Rinaldi, Simon Barry, Jan Hendrik Rüschoff, Marianna Sabbadin, Semini Sumanasuriya, Mateus Crespo, Adam Sharp, Wei Yuan, Mathew Grinu, Alexandra Boyle, Cynthia Miller, Lloyd Trotman, Nicolas Delaleu, Matteo Fassan, Holger Moch, Gabriella Viero, Johann de Bono, Andrea Alimonti
Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland., Yale Cancer Center and Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA., Institute of Biophysics, CNR Unit at Trento, Povo, Italy., Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland., IMED Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, UK., Department of Pathology and Molecular Pathology, University Hospital Zurich (USZ), Zurich, Switzerland., Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy., Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK., Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA., 2cSysBioMed, TI, Contra, Switzerland., Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/37460872