NK CELL STIMULATION OVERCOMES CASTRATION RESISTANCE OF PROSTATE TUMORS — ASN Events
  1. Schedule
  2. Poster Session One
  3. NK CELL STIMULATION OVERCOMES CASTRATION RESISTANCE OF PROSTATE TUMORS

NK CELL STIMULATION OVERCOMES CASTRATION RESISTANCE OF PROSTATE TUMORS (#111)

Léa Bouhelier 1 , Julie Terzic 1 2 , Lucie Maerky 1 , Graciela Ruiz 1 , Daniel Metzger 1
  1. IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire ; Centre National de la Recherche Scientifique (CNRS), UMR7104 ; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258 ; Université de Strasbourg , 1 rue Laurent Fries, 67400 Illkirch, France
  2. Present address: University of Geneva, 24 Rue du Général-Dufour, 1211 Geneva, Switzerland

Introduction

Prostate cancer (PCa) is one of the deadliest and the second most common cancer in western countries. It typically progresses over decades from prostatic intraepithelial neoplasia (PIN) to adenocarcinoma. At advanced stages, PCa is treated with androgen deprivation therapy. However, many patients eventually develop castration-resistant prostate cancer (CRPC) after an initial period of treatment responsiveness. While immunotherapies have recently become a significant cancer treatment, prostate cancer is a 'cold' tumor, unresponsive to most of such approaches. Therefore, it is crucial to identify new therapeutic strategies for CRPC patients.

As the tumor suppressor PTEN is frequently mutated in PCa, we generated genetically-engineered Pten(i)pe-/- mice in which Pten is selectively inactivated in adult prostatic epithelial cells. These mice develop PIN and CRPC characterized by an immunosuppressive microenvironment. In contrast, Pten/Hif1a(i)pe-/- mice, in which both Pten and Hif1a are inactivated, develop less aggressive tumors that are infiltrated with a higher numbers of natural killer (NK) cells, and are castration-sensitive. Thus, these findings indicate that HIF1α may contribute to tumor progression and castration resistance by inhibiting NK cell infiltration and/or NK cell-mediated cytotoxicity.

Methods

Pten/Hif1α(i)pe-/- mice were castrated and treated with anti-NK1.1 neutralizing antibodies for two weeks. Moreover, Pten(i)pe-/- mice were castrated or sham-operated and treated with IL-15 for three weeks. Prostate tumors were histologically analyzed.

Results

NK cells depletion in Pten/Hif1α(i)pe-/- mice via anti-NK1.1 antibodies induced castration resistance. Moreover, IL-15 treatment of castrated Pten(i)pe-/- mice promoted NK cells infiltration and/or proliferation, leading to partial castration sensitivity. In contrast, such a treatment had little effect on prostatic tumors of non-castrated Pten(i)pe-/- mice.

Conclusion

Our data show that NK cells stimulation boosts the anti-tumor immunity in CRPC after castration, and thus open new perspectives for personalized medicine.