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

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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.

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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

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Acknowledgments

We thank Ms Yoko Nakagawa, Yoko Mitobe and Yukiko Sugiyama for their skillful technical assistance. This work was partly supported by the Shimadzu Science Foundation, the Sagawa Foundation for Promotion of Cancer Research, Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, and the COE program of the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Correspondence to Shinya Kimura.

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T. Yuasa and K. Sato contributed equally to the study.

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Yuasa, T., Sato, K., Ashihara, E. et al. Intravesical administration of γδ T cells successfully prevents the growth of bladder cancer in the murine model. Cancer Immunol Immunother 58, 493–502 (2009). https://doi.org/10.1007/s00262-008-0571-9

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  • DOI: https://doi.org/10.1007/s00262-008-0571-9

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