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 (2014). Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell reports, 9(1), pp. 75-89. Cell Press 10.1016/j.celrep.2014.08.044

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Gynaecology

UniBE Contributor:

Marini, Camilla

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2211-1247

Publisher:

Cell Press

Language:

English

Submitter:

Nathalie Ursula Becher

Date Deposited:

13 May 2015 09:57

Last Modified:

14 May 2015 13:51

Publisher DOI:

10.1016/j.celrep.2014.08.044

PubMed ID:

25263564

BORIS DOI:

10.7892/boris.68903

URI:

https://boris.unibe.ch/id/eprint/68903

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