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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author 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,
Project Manipulation of senescence pathways for cancer therapy: from experimental models to clinic
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Original article (peer-reviewed)

Journal Cell reports
Volume (Issue) 9(1)
Page(s) 75 - 89
Title of proceedings Cell reports
DOI 10.1016/j.celrep.2014.08.044

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.
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