title: Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity.
abstract: Prosenescence therapy has recently emerged as a novel therapeutic approach for treating cancer. However, this concept is challenged by conflicting evidence showing that the senescence-associated secretory phenotype (SASP) of senescent tumor cells can have pro- as well as antitumorigenic effects. Herein, we report that, in Pten-null senescent tumors, activation of the Jak2/Stat3 pathway establishes an immunosuppressive tumor microenvironment that contributes to tumor growth and chemoresistance. Activation of the Jak2/Stat3 pathway in Pten-null tumors is sustained by the downregulation of the protein tyrosine phosphatase PTPN11/SHP2, providing evidence for the existence of a novel PTEN/SHP2 axis. Importantly, treatment with docetaxel in combination with a JAK2 inhibitor reprograms the SASP and improves the efficacy of docetaxel-induced senescence by triggering a strong antitumor immune response in Pten-null tumors. Altogether, these data demonstrate that immune surveillance of senescent tumor cells can be suppressed in specific genetic backgrounds but also evoked by pharmacological treatments.
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland.
authors.forename: Alberto
authors.initials: A
authors.lastname: Toso
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland; Faculty of Biology and Medicine, University of Lausanne, UNIL, Rue du Bugnon 21, Lausanne 1011, Switzerland.
authors.forename: Ajinkya
authors.initials: A
authors.lastname: Revandkar
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland.
authors.forename: Diletta
authors.initials: D
authors.lastname: Di Mitri
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Guccini
authors.affiliation: Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland.
authors.forename: Michele
authors.initials: M
authors.lastname: Proietti
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sarti
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pinton
authors.affiliation: Faculty of Arts and Sciences (FAS), Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Jiangwen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland; Faculty of Biology and Medicine, University of Lausanne, UNIL, Rue du Bugnon 21, Lausanne 1011, Switzerland.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Kalathur
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Civenni
authors.affiliation: Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Jarrossay
authors.affiliation: Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland.
authors.forename: Erica
authors.initials: E
authors.lastname: Montani
authors.affiliation: Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland.
authors.forename: Camilla
authors.initials: C
authors.lastname: Marini
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland; Molecular Oncology Unit, CIEMAT, Madrid 28040, Spain; Oncogenomics Unit, Institute of Biomedical Research, Hospital "12 de Octubre", 28041 Madrid, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Garcia-Escudero
authors.affiliation: Department of Animal Pathology, University of Milan, Milan 20139, Italy; Mouse and Animal Pathology Laboratory, Fondazione Filarete, Milan 20139, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Scanziani
authors.affiliation: Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland.
authors.forename: Fabio
authors.initials: F
authors.lastname: Grassi
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland.
authors.forename: Carlo V
authors.initials: CV
authors.lastname: Catapano
authors.affiliation: Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland; Faculty of Biology and Medicine, University of Lausanne, UNIL, Rue du Bugnon 21, Lausanne 1011, Switzerland. Electronic address: andrea.alimonti@ior.iosi.ch.
authors.forename: Andrea
authors.initials: A
authors.lastname: Alimonti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016922:Cellular Senescence / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D000077143:Docetaxel; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D043823:Taxoids / Q000494:pharmacology; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D043823:Taxoids; D000077143:Docetaxel; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse