Login to Access Video or Poster Abstract: MP98-06
Sources of Funding: none

Introduction

Mycobacterium bovis bacillus Calmette-Guerin (BCG) has been used for the treatment of bladder cancer for almost 40 years, although the antitumor effector mechanisms remain elusive. Recent our study demonstrated interleukin (IL)-17 produced by γδT cells plays a key role in the recruitment of neutrophlis to the bladder after BCG instillation, which is important for the antitumor activity against bladder tumor. And, other studies reported that IL-15 plays an important role in neutrophil migration during inflammation. In the present study, we constructed a recombinant BCG expressing the fusion protein of IL-15 (BCG-IL-15) and examined the efficacy of BCG-IL-15 in providing protection against bladder cancer.

Methods

Six-week-old female C57BL/6 (B6) mice or CδKO mice (B6 background) were intravesically inoculated with 2 x 105 bladder tumor cells (MB49 cells) on day 0. On day 1, 8, 15, and 22 after tumor implantation, mice were inoculated intravesically with either 2 x 106 BCG-IL-15, BCG or PBS weekly.

Results

BCG-IL-15 treatment prolonged the survival of mice inoculated with bladder cancer cells, compared with BCG treatmnet. We analyzed the effector cells (neutrophils and γδ T cells), which were reported to play key roles in the anti-tumor response. We found infiltration of neutrophil and γδ T cells were significantly elevated in BCG-IL-15 treated mice. Moreover, we confirmed the importance of neutrophils and γδT cells in antitumor effect of BCG-IL-15 therapy by depleting neutrophils with anti Gr-1 antibody and using γδ T cells KO mice (Cδ KO mice). To examine whether IL-17 production was induced by intravesical instillations of BCG-IL-15, we measured vesical IL-17 production by ELISA. IL-17 production after BCG-IL-15 treatment was significantly increased. Moreover, although we previously reported TCRγδand CD25-positive population were IL-17 producing γδT cells, the percentage and the absolute number of TCRγδ and CD25-positive cells of BCG-IL-15-treated mice significantly increased.

Conclusions

These results suggested that IL-17 produced by γδT cells and chemokines (MIP-2 and MIP-1) induced by BCG-IL-15 played a key role in the recruitment of neutrophlis to the bladder wall. And we believe BCG-IL-15 can become one of the promising drugs for the non muscle invasive bladder cancer.

Funding

none