Intravesical administration of gammadelta T cells successfully prevents the growth of bladder cancer in the murine model

Cancer Immunol Immunother. 2009 Apr;58(4):493-502. doi: 10.1007/s00262-008-0571-9. Epub 2008 Aug 6.

Abstract

Background: Superficial bladder cancers are usually managed with transurethral resection followed by the intravesical administration of Bacillus Calmette-Guerin which requires major histocompatibility complex (MHC) class I expression on cancer cells. Since cancer cells often loose MHC expression, a novel immunotherapy such as MHC-unrestricted gammadelta T cell therapy is desired.

Objective: To clarify the relationship between the expression of MHC class I and clinicopathological features in bladder cancer patients, and investigate the effects of the administration of intravesical gammadelta T cells on bladder cancer.

Methods: Samples from 123 patients who had undergone either transurethral resection or radical cystectomies were examined for MHC expression and the relationship between this and the clinicopathological features was analyzed statistically. The in vitro and in vivo effects of gammadelta T cells expanded by zoledronic acid (ZOL) against several types of cancer cell line and an orthotopic bladder cancer murine model which was pretreated with ZOL were investigated.

Results: MHC-diminished superficial bladder cancer was significantly more progressive than MHC-conservative bladder cancer (P = 0.047). In addition, there was a significant association between diminished MHC expression and poor disease free survival (P = 0.041) and overall survival (P = 0.018) after radical cystectomy. In vitro, all of the cell lines pretreated with 5-microM ZOL showed a marked increase in sensitivity to lysis by gammadelta T cells. Moreover, intravesical administration of gammadelta T cells with 5-microM ZOL significantly demonstrated antitumor activity against bladder cancer cells in the orthotopic murine model (P < 0.001), resulting in prolonged survival.

Conclusion: The present murine model provides a potentially interesting option to develop immunotherapy using gammadelta T cells for bladder cancer in human.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravesical
  • Aged
  • Animals
  • Blotting, Western
  • Diphosphonates / pharmacology
  • Female
  • Histocompatibility Antigens Class I / biosynthesis*
  • Humans
  • Imidazoles / pharmacology
  • Immunohistochemistry
  • Immunologic Factors / pharmacology
  • Immunotherapy, Adoptive / methods*
  • Kaplan-Meier Estimate
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Prognosis
  • Receptors, Antigen, T-Cell, gamma-delta / immunology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes / immunology*
  • Urinary Bladder Neoplasms / immunology*
  • Urinary Bladder Neoplasms / pathology
  • Urinary Bladder Neoplasms / therapy*
  • Zoledronic Acid

Substances

  • Diphosphonates
  • Histocompatibility Antigens Class I
  • Imidazoles
  • Immunologic Factors
  • Receptors, Antigen, T-Cell, gamma-delta
  • Zoledronic Acid