Tumor cells promote the recruitment of immunosuppressive neutrophils, a subset of myeloid cells driving immune suppression, tumor proliferation, and treatment resistance. Physiologically, neutrophils are known to have a short half-life. Here, we report the identification of a subset of neutrophils that have upregulated expression of cellular senescence markers and persist in the tumor microenvironment. Senescent-like neutrophils express the triggering receptor expressed on myeloid cells 2 (TREM2) and are more immunosuppressive and tumor-promoting than canonical immunosuppressive neutrophils. Genetic and pharmacological elimination of senescent-like neutrophils decreases tumor progression in different mouse models of prostate cancer. Mechanistically, we have found that apolipoprotein E (APOE) secreted by prostate tumor cells binds TREM2 on neutrophils, promoting their senescence. APOE and TREM2 expression increases in prostate cancers and correlates with poor prognosis. Collectively, these results reveal an alternative mechanism of tumor immune evasion and support the development of immune senolytics targeting senescent-like neutrophils for cancer therapy.
Cancer cell. 2023 Feb 22 [Epub ahead of print]
Nicolò Bancaro, Bianca Calì, Martina Troiani, Angela Rita Elia, Rydell Alvarez Arzola, Giuseppe Attanasio, Ping Lai, Mateus Crespo, Bora Gurel, Rita Pereira, Christina Guo, Simone Mosole, Daniela Brina, Mariantonietta D'Ambrosio, Emiliano Pasquini, Clarissa Spataro, Elena Zagato, Andrea Rinaldi, Mattia Pedotti, Simona Di Lascio, Francesco Meani, Monica Montopoli, Matteo Ferrari, Andrea Gallina, Luca Varani, Ricardo Pereira Mestre, Marco Bolis, Silke Gillessen Sommer, Johann de Bono, Arianna Calcinotto, Andrea Alimonti
Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland., The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK., Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland; Institute for Research in Biomedicine (IRB), 6500 Bellinzona, Switzerland., Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland; Institute of Oncology of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland., Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy; Veneto Institute of Molecular Medicine, Padova, Italy., Department of Urology, Ente Ospedaliero Cantonale, Ospedale Regionale di Lugano - Civico USI - Università della Svizzera Italiana, Lugano, Switzerland., Institute for Research in Biomedicine (IRB), 6500 Bellinzona, Switzerland., Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland; Institute of Oncology of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland., Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland; Computational Oncology Unit, Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche 'Mario Negri', Via Mario Negri 2, 20156 Milano, Italy., Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland. Electronic address: ., Institute of Oncology Research (IOR), 6500 Bellinzona, Switzerland; Università della Svizzera Italiana, Faculty of Biomedical Sciences, 6900 Lugano, Switzerland; Institute of Oncology of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland; Veneto Institute of Molecular Medicine, Padova, Italy; Department of Medicine, University of Padova, Padova, Italy; Department of Health Sciences and Technology (D-HEST) ETH Zurich, 8093 Zurich, Switzerland. Electronic address: .