Remodeling the bladder tumor immune microenvironment by mycobacterial species with changes in their cell envelope composition
Senserrich, Jordi (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Guallar Garrido, Sandra (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Gomez-Mora, Elisabet (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Urrea, Víctor (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Clotet Sala, Bonaventura (Centro de Investigación Biomédica en Red de Enfermedades Infecciosas)
Julián Gómez, Esther (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Cabrera Navarro, Cecilia (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)

Date:	2022
Abstract:	Intravesical BCG instillation after bladder tumor resection is the standard treatment for non-muscle invasive bladder cancer; however, it is not always effective and frequently has undesirable side effects. Therefore, new strategies that improve the clinical management of patients are urgently needed. This study aimed to comprehensively evaluate the bladder tumor immune microenvironment profile after intravesical treatment with a panel of mycobacteria with variation in their cell envelope composition and its impact on survival using an orthotopic murine model to identify more effective and safer therapeutic strategies. tumor-bearing mice were intravesically treated with a panel of BCG and M. brumae cultured under different conditions. Untreated tumor-bearing mice and healthy mice were also included as controls. After mycobacterial treatments, the infiltrating immune cell populations in the bladder were analysed by flow cytometry. We provide evidence that mycobacterial treatment triggered a strong immune infiltration into the bladder, with BCG inducing higher global absolute infiltration than M. brumae. The induced global immune microenvironment was strikingly different between the two mycobacterial species, affecting both innate and adaptive immunity. Compared with M. brumae, BCG treated mice exhibited a more robust infiltration of CD4 + and CD8 + T-cells skewed toward an effector memory phenotype, with higher frequencies of NKT cells, neutrophils/gMDSCs and monocytes, especially the inflammatory subset, and higher CD4 + T/CD4 + T and CD8 + T/CD4 + T ratios. Conversely, M. brumae treatment triggered higher proportions of total activated immune cells and activated CD4 + and CD8 + T cells and lower ratios of CD4 + T cells/CD4 + T, CD8 + T cells/CD4 + T and inflammatory/reparative monocytes. Notably, the mycobacterial cell envelope composition in M. brumae had a strong impact on the immune microenvironment, shaping the B and myeloid cell compartment and T-cell maturation profile and thus improving survival. Overall, we demonstrate that the bladder immune microenvironment induced by mycobacterial treatment is species specific and shaped by mycobacterial cell envelope composition. Therefore, the global bladder immune microenvironment can be remodelled, improving the quality of infiltrating immune cells, the balance between inflammatory and regulatory/suppressive responses and increasing survival.
Grants:	Ministerio de Ciencia e Innovación RTI2018-098777-B-I00 Generalitat de Catalunya 2017SGR-229
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Non-muscle invasive bladder cancer ; Bcg ; Mycobacterium brumae ; Immunotherapy ; Intravesical mycobacterial treatment ; Tumor immune microenvironment
Published in:	Frontiers in immunology, Vol. 13 (october 2022) , ISSN 1664-3224

DOI: 10.3389/fimmu.2022.993401
PMID: 36304456

16 p, 7.2 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Articles > Research articles
Articles > Published articles