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Cell Rep. 2014 Oct 9;9(1):75-89. doi: 10.1016/j.celrep.2014.08.044. Epub 2014 Sep 25.

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

Author information

1
Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland.
2
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.
3
Institute for Research in Biomedicine (IRB), Bellinzona 6500, Switzerland.
4
Faculty of Arts and Sciences (FAS), Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA.
5
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.
6
Department of Animal Pathology, University of Milan, Milan 20139, Italy; Mouse and Animal Pathology Laboratory, Fondazione Filarete, Milan 20139, Italy.
7
Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
8
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.

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.

PMID:
25263564
DOI:
10.1016/j.celrep.2014.08.044
[Indexed for MEDLINE]
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