The Journal of Urology
Volume 181, Issue 1 , Pages 354-362, January 2009

PTEN Knockout Prostate Cancer as a Model for Experimental Immunotherapy

  • Kazunori Haga

      Affiliations

    • Department of Medicine, University of California-Los Angeles, California
    • Equal study contribution.
    • ,
  • Atsushi Tomioka

      Affiliations

    • Department of Medicine, University of California-Los Angeles, California
    • Department of Urology, Nara Medical University, Nara, Japan
    • Equal study contribution.
    • ,
  • Chun-Peng Liao

      Affiliations

    • Departments of Pathology, and Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California
    • ,
  • Takahiro Kimura

      Affiliations

    • Department of Medicine, University of California-Los Angeles, California
    • Department of Urology, Jikei Medical University, Tokyo, Japan
    • ,
  • Hiroshi Matsumoto

      Affiliations

    • Department of Medicine, University of California-Los Angeles, California
    • ,
  • Izumi Ohno

      Affiliations

    • Department of Medicine, University of California-Los Angeles, California
    • ,
  • Kip Hermann

      Affiliations

    • Department of Medicine, University of California-Los Angeles, California
    • ,
  • Christopher R. Logg

      Affiliations

    • Department of Medicine, University of California-Los Angeles, California
    • ,
  • Jing Jiao

      Affiliations

    • Department of Molecular and Medical Pharmacology, University of California-Los Angeles, California
    • ,
  • Motoyoshi Tanaka

      Affiliations

    • Department of Urology, Kinki University, Osaka, Japan
    • ,
  • Yoshihiko Hirao

      Affiliations

    • Department of Urology, Nara Medical University, Nara, Japan
    • ,
  • Hong Wu

      Affiliations

    • Department of Medicine, University of California-Los Angeles, California
    • Department of Molecular and Medical Pharmacology, University of California-Los Angeles, California
    • ,
  • Carol A. Kruse

      Affiliations

    • Sidney Kimmel Cancer Center, San Diego, California
    • ,
  • Pradip Roy-Burman

      Affiliations

    • Departments of Pathology, and Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California
    • ,
  • Noriyuki Kasahara

      Affiliations

    • Department of Medicine, University of California-Los Angeles, California
    • Department of Molecular and Medical Pharmacology, University of California-Los Angeles, California
    • Corresponding Author InformationCorrespondence and requests for reprints: Department of Medicine, University of California-Los Angeles, 675 Charles E. Young Dr. South, MRL-1551, Los Angeles, California 90095 (telephone: 310-825-7112; FAX: 310-825-5204)

Received 2 April 2008 published online 17 November 2008.

Purpose

Testing immunotherapeutic strategies for prostate cancer has been impeded by the lack of relevant tumor models in immunocompetent animals. This opportunity is now provided by the recent development of prostate specific PTEN knockout mice, which show spontaneous development of true adenocarcinoma arising from prostate epithelium and more faithfully recapitulate the human disease than any previous model. We investigated the feasibility of using tumor cells derived from this model to test tumor vaccination and adoptive immunotherapeutic strategies for prostate cancer.

Materials and Methods

PTEN-CaP8 adenocarcinoma cells derived from the biallelic PTEN knockout prostate cancer model were used to vaccinate nontumor bearing litter mates. Tumor specific effector cells were generated from splenocytes of vaccinated mice by mixed lymphocyte-tumor reactions, and antiproliferative effects and cytokine generation were examined in vitro. The effect of vaccination or adoptive immunotherapy on luciferase marked PTEN-CaP8 subcutaneous tumors was monitored by tumor volumetric measurements and noninvasive bioluminescence imaging.

Results

Vaccination of litter mate mice with irradiated PTEN-CaP8 cells showed a significant prophylactic effect against the subsequent tumor challenge. Effector cells harvested from vaccinated litter mates showed significant interferon-γ secretion upon co-incubation with PTEN-CaP8 target cells and they were capable of efficient target cell growth inhibition in vitro. Intratumor adoptive transfer of effector cells resulted in significant growth inhibition of preestablished prostate tumors in vivo.

Conclusions

The PTEN knockout model serves as a highly useful model in which to investigate tumor cell vaccination and adoptive immunotherapeutic strategies in the context of true adenocarcinoma of the prostate. This model should accelerate efforts to develop effective immunotherapies for human prostate cancer.

Key Words: prostate, prostatic neoplasms, PLIP protein, mouse, cancer vaccines, immunotherapy, adoptive

Abbreviations and Acronyms: ADI-Ca, androgen depletion independent cancer, CTL, cytotoxic T lymphocyte, ELISA, enzyme-linked immunosorbent assay, E/T, effector-to-target, GFP, green fluorescent protein, IFN-γ, interferon-γ, MLTR, mixed lymphocyte-tumor reaction, MTS, (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium, PBS, phosphate buffered saline, PTEN, phosphatase and tensin homologue deleted on chromosome 10, ROI, region of interest, RL, Renilla luciferase

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 Study received approval from University of California-Los Angeles and University of Southern California (Project No. 2003-120-12).

 Supported by National Institutes of Health Grants R01 CA121258 (NK), R01 CA059705 and R01 CA113392 (PRB), Idea Award PC074133 (NK and PRB) and Post-Doctoral Training Award PC073547 (KH) from the Department of Defense Prostate Cancer Research Program, and Developmental Research Program seed grant from the University of California-Los Angeles Specialized Program of Research Excellence in Prostate Cancer (NK).

PII: S0022-5347(08)02416-6

doi:10.1016/j.juro.2008.08.124

The Journal of Urology
Volume 181, Issue 1 , Pages 354-362, January 2009

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