Combination of novel intravesical xenogeneic urothelial cell immunotherapy and chemotherapy enhances anti-tumor efficacy
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ORIGINAL ARTICLE
Combination of novel intravesical xenogeneic urothelial cell immunotherapy and chemotherapy enhances anti‑tumor efficacy in preclinical murine bladder tumor models Chi‑Ping Huang1 · Chun‑Chie Wu1 · Chih‑Rong Shyr2 Received: 20 April 2020 / Accepted: 20 October 2020 © The Author(s) 2020
Abstract Background Immune checkpoint inhibitors induce robust and durable responses in advanced bladder cancer (BC), but only for a subset of patients. Xenovaccination has been proposed as an effective immunotherapeutic approach to induce anti-tumor immunity. Thus, we proposed a novel intravesical xenogeneic urothelial cell immunotherapy strategy to treat advanced BC based on the hypothesis that implanted xenogeneic urothelial cells not only provoke xeno-rejection immune responses but also elicit bystander anti-tumor immunity. Methods Mouse advanced bladder cancer models were treated with vehicle control, intravesical xenogeneic urothelial cells, cisplatin + gemcitabine, or the combination and assessed for tumor responses to treatments. Tumors and spleens samples were collected for immunohistological staining, cellular and molecular analysis assessed by antibody staining, ELISA, cytotoxicity, and flow cytometry, respectively. Results The combination treatment of xenogeneic urothelial cell immunotherapy with chemotherapy was more efficacious than either single therapy to extend survival time in MBT-2 graft bladder tumor model and to suppress tumor progression in murine carcinogen BBN-induced bladder tumor model. The single-cell immunotherapy and combined therapy increased more tumor-infiltrating immune cells in MBT-2 graft tumors compared to vehicle control and chemotherapy treatment groups. The activated T-cell proliferation, cytokine production, and cytotoxicity capacities were also higher in mice with xenogeneic urothelial cell immunotherapy and combination treatments. Conclusions Our results suggest the potential for a novel xenogeneic urothelial cell-based immunotherapy alone and synergy with chemotherapy in the combination therapy. Therefore, our study supports developing xenogeneic urothelial cells as an immunotherapeutic agent in combination with chemotherapy for BC treatment. Keywords Xenotransplantation · Rejection · Immunity · Xenoantigen · Neoantigen Abbreviations BBN N-Butyl-N-(4-hydroxybutyl)-nitrosamine BC Bladder cancer BCG Bacillus Calmette–Guérin Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02775-6) contains supplementary material, which is available to authorized users. * Chih‑Rong Shyr [email protected] 1
Division of Urology, China Medical University and Hospital, Taiwan, Republic of China
Department of Medical Laboratory Science and Biotechnology, Sex Hormone Research Center, China Medical University and Hospital, Taiwan, Republic of China
2
BLI Bioluminescence imaging CFDA-SE Carboxyfluorescein diacetate succinimidyl ester CIS Carcinoma in situ GC Gemcitabine plus cisplatin IFN Interferon IHC Immunoh
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