Enhancing Chemotherapy Efficacy in Pten-Deficient Prostate Tumors by Activating the Senescence-Associated Antitumor Immunity

Abstract

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. : Cytokines released by senescent cells can have pro- as well as antitumorigenic effects. Here, Toso et al. show that cytokines released by Pten-null senescent prostate tumors drive an immunosuppressive tumor microenvironment. Pharmacological inhibition of the Jak2/Stat3 pathway in Pten-deficient prostate tumors reprograms the senescence-associated cytokine network, leading to an antitumor immune response that enhances chemotherapy efficacy. These data demonstrate that immune surveillance of senescent tumor cells can be suppressed in specific genetic backgrounds but is also evoked by pharmacological treatments.