Topical and systemic immunoreaction triggered by intravesical chemotherapy in an N-butyl-N-(4-hydroxybutyl) nitorosamine induced bladder cancer mouse model.

Shunta Hori,Yosuke Morizawa,Sayuri Onishi,Yoshihiro Tatsumi,Yasushi Nakai,Nobumichi Tanaka,Kiyohide Fujimoto,Makito Miyake,Aamir Ahmad

doi:10.1371/journal.pone.0175494

Shunta Hori, Yosuke Morizawa + Show 7 more

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https://doi.org/10.1371/journal.pone.0175494

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Journal: PloS one	Publication Date: Apr 13, 2017
Citations: 13	License type: CC BY 4.0

Affiliation: Nara Medical University

Abstract

Intravesical bacillus Calmette-Guerin (BCG) treatment is the most common therapy to prevent progression and recurrence of non-muscle invasive bladder cancer (NMIBC). Although the immunoreaction elicited by BCG treatment is well documented, those induced by intravesical treatment with chemotherapeutic agents are much less known. We investigated the immunological profiles caused by mitomycin C, gemcitabine, adriamycin and docetaxel in the N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced orthotopic bladder cancer mouse model. Ninety mice bearing orthotopic bladder cancer induced by BBN were randomly divided into six groups and treated with chemotherapeutic agents once a week for four weeks. After last treatment, bladder and serum samples were analyzed for cell surface and immunological markers (CD4, CD8, CD56, CD204, Foxp3, and PD-L1) using immunohistochemistry staining. Serum and urine cytokine levels were evaluated by ELISA. All chemotherapeutic agents presented anti-tumor properties similar to those of BCG. These included changes in immune cells that resulted in fewer M2 macrophages and regulatory T cells around tumors. This result was compatible with those in human samples. Intravesical chemotherapy also induced systemic changes in cytokines, especially urinary interleukin (IL)-17A and granulocyte colony stimulating factor (G-CSF), as well as in the distribution of blood neutrophils, lymphocytes, and monocytes. Our findings suggest that intravesical treatment with mitomycin C and adriamycin suppresses protumoral immunity while enhancing anti-tumor immunity, possibly through the action of specific cytokines. A better understanding of the immunoreaction induced by chemotherapeutic agents can lead to improved outcomes and fewer side effects in intravesical chemotherapy against NMIBC.

Highlights

Urothelial carcinoma of the bladder (UCB) is the fourth and eighth most common malignancy in men and women, respectively, in the United States
non-muscle invasive bladder cancer (NMIBC) is treated by transurethral resection of the bladder tumor (TURBT), followed by the administration of adjuvant intravesical treatment with bacillus Calmette-Guerin (BCG) or chemotherapeutic agents, such as adriamycin (ADM), mitomycin C (MMC), gemcitabine (GEM), or docetaxel (DTX) [4, 5]
Given that serum granulocyte colony stimulating factor (G-CSF) increased in the BCG, MMC, ADM, and DTX groups, all of which presented anti-tumor activity in a butylN-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder cancer model, we suggest that the anti-tumor activity of G-CSF relies on neutrophil induction

Summary

Introduction

Urothelial carcinoma of the bladder (UCB) is the fourth and eighth most common malignancy in men and women, respectively, in the United States. 70% of UCB cases are diagnosed as non-muscle invasive bladder cancer (NMIBC), including stages Ta and T1 [2, 3]. NMIBC is treated by transurethral resection of the bladder tumor (TURBT), followed by the administration of adjuvant intravesical treatment with bacillus Calmette-Guerin (BCG) or chemotherapeutic agents, such as adriamycin (ADM), mitomycin C (MMC), gemcitabine (GEM), or docetaxel (DTX) [4, 5]. These intravesical treatments can decrease recurrence rates and prolong the progression-free interval [6, 7]. The aim of NMIBC clinical management is to prevent cancer progression and recurrence

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