Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity

Toso, Alberto; Revandkar, Ajinkya; Di Mitri, Diletta; Guccini, Ilaria; Proietti, Michele; Sarti, Manuela; Pinton, Sandra; Zhang, Jiangwen; Kalathur, Madhuri; Civenni, Gianluca; Jarrossay, David; Montani, Erica; Marini, Camilla; Garcia-Escudero, Ramon; Scanziani, Eugenio; Grassi, Fabio; Pandolfi, Pier Paolo; Catapano, Carlo V.; Alimonti, Andrea

doi:10.1016/j.celrep.2014.08.044

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Journal article

Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity

Toso, Alberto Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
Revandkar, Ajinkya Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland - Faculty of Biology and Medicine, University of Lausanne, UNIL, Rue du Bugnon 21, Lausanne 1011, Switzerland
Di Mitri, Diletta Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
Guccini, Ilaria Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
Proietti, Michele Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Sarti, Manuela Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
Pinton, Sandra Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
Zhang, Jiangwen Faculty of Arts and Sciences (FAS), Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA
Kalathur, Madhuri Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland - Faculty of Biology and Medicine, University of Lausanne, UNIL, Rue du Bugnon 21, Lausanne 1011, Switzerland
Civenni, Gianluca Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
Jarrossay, David Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Montani, Erica Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Marini, Camilla Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Garcia-Escudero, Ramon Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland - Molecular Oncology Unit, CIEMAT, Madrid 28040, Spain - Oncogenomics Unit, Institute of Biomedical Research, Hospital ‘‘12 de Octubre’’, 28041 Madrid, Spain
Scanziani, Eugenio Department of Animal Pathology, University of Milan, Milan 20139, Italy - Mouse and Animal Pathology Laboratory, Fondazione Filarete, Milan 20139, Italy
Grassi, Fabio Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Pandolfi, Pier Paolo Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard
Catapano, Carlo V. Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
Alimonti, Andrea Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland - Faculty of Biology and Medicine, University of Lausanne, UNIL, Rue du Bugnon 21, Lausanne 1011, Switzerland

09.10.2014

Published in:

Cell reports. - 2014, vol. 9, no. 1, p. 75-89

English 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.

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