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

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.

• Authors: Bo Wang, Zhihua He, Hao Yu, Ziwei Ou, Junyu Chen, Meihua Yang, Xinxiang Fan, Tianxin Lin, Jian Huang
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 71 Issue 6 Pg. 1507-1517 (Jun 2022) ISSN: 1432-0851 [Electronic] Germany
• PMID: 34718847 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• Adjuvants, Immunologic
• B7-H1 Antigen
• BCG Vaccine
• Hemagglutinins
• Hepatitis A Virus Cellular Receptor 2
• Programmed Cell Death 1 Receptor
• Mannose

Topics

• Adjuvants, Immunologic (therapeutic use)
• Administration, Intravesical
• Animals
• B7-H1 Antigen (therapeutic use)
• BCG Vaccine (therapeutic use)
• Carcinoma, Transitional Cell
• Disease Models, Animal
• Hemagglutinins (therapeutic use)
• Hepatitis A Virus Cellular Receptor 2
• Humans
• Mannose (therapeutic use)
• Mice
• Mycobacterium bovis
• Programmed Cell Death 1 Receptor (therapeutic use)
• Pseudomonas aeruginosa
• Urinary Bladder Neoplasms (drug therapy)