[HTML][HTML] Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity
Cell reports, 2014•cell.com
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 …
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 …
Summary
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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