Cancer Immunology, Immunotherapy

, Volume 58, Issue 4, pp 493–502

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

  • Takeshi Yuasa
  • Kiyoshi Sato
  • Eishi Ashihara
  • Miki Takeuchi
  • Shinya Maita
  • Norihiko Tsuchiya
  • Tomonori Habuchi
  • Taira Maekawa
  • Shinya Kimura
Original Article

DOI: 10.1007/s00262-008-0571-9

Cite this article as:
Yuasa, T., Sato, K., Ashihara, E. et al. Cancer Immunol Immunother (2009) 58: 493. doi:10.1007/s00262-008-0571-9

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

Conclusion

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

Keywords

Bladder cancer Intravesical administration Major histocompatibility complex γδ T Zoledronic acid 

Abbreviations

BCG

Bacillus Calmette-Guerin

CIs

Confidence intervals

CIS

Carcinoma in situ

51Cr

51 Chromium

CTL

Cytotoxic T-lymphocytes.

E/T

Effecter/target cell

IL-2

Interleukin-2

IVIS

In vivo imaging system

HRs

Hazard ratios

Luc

Luciferase

MHC

Major histocompatibility complex

NK

Natural killer

PBMCs

Peripheral blood mononuclear cells

SCID

Severe combined immunodeficiency

siRNA

Small interfering RNA

TUR

Transurethral resection

ZOL

Zoledronic acid

Supplementary material

262_2008_571_MOESM1_ESM.pdf (16 kb)
Supplemental Fig. 1 Schematic diagram of the mevalonate pathway and site of action of ZOL (PDF 15 kb)

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Takeshi Yuasa
    • 1
  • Kiyoshi Sato
    • 2
  • Eishi Ashihara
    • 2
  • Miki Takeuchi
    • 2
  • Shinya Maita
    • 1
  • Norihiko Tsuchiya
    • 1
  • Tomonori Habuchi
    • 1
  • Taira Maekawa
    • 2
  • Shinya Kimura
    • 2
  1. 1.Department of UrologyAkita University School of MedicineAkitaJapan
  2. 2.Department of Transfusion Medicine and Cell TherapyKyoto University HospitalKyotoJapan