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Intravesical Pseudomonas aeruginosa mannose-sensitive Hemagglutinin vaccine triggers a tumor-preventing immune environment in an orthotopic mouse bladder cancer model

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Abstract

Bacillus Calmette-Guerin (BCG) immunotherapy can prevent recurrence and progression in selected patients with non-muscle-invasive bladder cancer (NMIBC); however, significant adverse events and treatment failure suggest the need for alternative agents. A commercial anti-infection vaccine comprises a genetically engineered heat-killed Pseudomonas aeruginosa (PA) expressing many mannose-sensitive hemagglutination (MSHA) fimbriae, termed PA-MSHA, which could be a candidate for bladder cancer intravesical therapy. In an immunocompetent orthotopic MB49 bladder cancer model, we characterized the antitumor effects and mechanisms of PA-MSHA compared with those of BCG. Three weekly intravesical PA-MSHA or BCG treatments reduced tumor involvement; however, only PA-MSHA prolonged survival against MB49 implantation significantly. In non-tumor-bearing mice after treatment, flow-cytometry analysis showed PA-MSHA and BCG induced an increased CD4/CD8 ratio, the levels of effector memory T cell phenotypes (CD44, CXCR-3, and IFN-γ), and the proportion of CD11b+Ly6G−Ly6C−IA/IE+ mature macrophages, but a decrease in the proportion of CD11b+Ly6G−Ly6C+IA/IE− monocytic myeloid-derived suppressor cells (Mo-MDSCs) and the expression of suppressive molecules on immune cells (PD-L1, PD-1, TIM-3, and LAG-3). Notably, PA-MSHA, but not BCG, significantly reduced PD-1 and TIM-3 expression on CD4+ T cells, which might account for the better effects of PA-MSHA than BCG. However, in tumor-bearing mice after treatment, the increased proportion of Mo-MDSCs and high expression of PD-L1 might be involved in treatment failure. Thus, modulating the balance among adaptive and innate immune responses was identified as a key process underlying PA-MSHA-mediated treatment efficacy. The results demonstrated mechanisms underlying intravesical PA-MSHA therapy, pointing at its potential as an alternative effective treatment for NMIBC.

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Acknowledgements

We thank the Wanter Biopharma Company (Beijing, China) and Chengdu Institute of Biological Products Co., Ltd (Chengdu, China) for providing PA-MSHA and BCG, respectively.

This study was supported by the National Natural Science Foundation of China (Grant No. 2018YFA0902803 and 81,825,016); the Science and Technology Program of Guangzhou (Grant No. 201604020156); the Pearl River S&T Nova Program of Guangzhou (201,806,010,024); Fundamental Research Funds for Young Teachers in the Higher Education Institutions of China (Grant No. 19ykpy116); the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-Sen University (Grant No. KLB09001); the Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology (Grant No. 013–163); the Key Science Research Projects of Gannan Medical University in 2018 (Grant No. ZD201835); and Science and Technology Plan Project of Jiangxi Provincial Health Committee (Grant No. 20204519).

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  1. Bo Wang and Zhihua He contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen (Zhongshan) University, Guangzhou, 510120, People’s Republic of China

    Bo Wang, Zhihua He, Hao Yu, Ziwei Ou, Junyu Chen, Meihua Yang, Xinxiang Fan, Tianxin Lin & Jian Huang

  2. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China

    Bo Wang, Tianxin Lin & Jian Huang

  3. Department of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, People’s Republic of China

    Zhihua He

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  1. Bo Wang
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Contributions

Wang B and He Z designed the experiment, analyzed the data, and wrote the manuscript; Yu H and Fan X established the mice models and performed the treatments; Yang M and Ou Z collected the samples and do the flow cytometric analysis; Chen J did the histology stains; Lin T modified and revised the manuscript; Huang J supervised in the design of the study and finalized the manuscript. All authors have read and approved the manuscript and agree with their inclusion as a co-author.

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Correspondence to Tianxin Lin or Jian Huang.

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Ethical approval was provided by the Committees for Ethical Review of Research at Sun Yat-sen University and was performed according to the institutional ethical guidelines for animal experiments.

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Wang, B., He, Z., Yu, H. et al. Intravesical Pseudomonas aeruginosa mannose-sensitive Hemagglutinin vaccine triggers a tumor-preventing immune environment in an orthotopic mouse bladder cancer model. Cancer Immunol Immunother 71, 1507–1517 (2022). https://doi.org/10.1007/s00262-021-03063-7

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