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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cellular Senescence / immunology
  • Cytokines / immunology
  • Docetaxel
  • Female
  • Gene Expression Profiling
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • PTEN Phosphohydrolase / deficiency*
  • PTEN Phosphohydrolase / immunology*
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / immunology*
  • Prostatic Neoplasms / pathology
  • Signal Transduction
  • Taxoids / pharmacology
  • Tumor Microenvironment


  • Antineoplastic Agents
  • Cytokines
  • Taxoids
  • Docetaxel
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Pten protein, mouse