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Impact of ageing on the immunotherapy effect of mycobacteria against cancer

P Herrero-Abadía(1) J Pagès(2,3) C Cabrera(2,3) E Julián(1)

1:Universitat Autònoma de Barcelona; 2:Irsicaixa; 3:Institute for Health Science Research Germans Trias i Pujol (IGTP)

Due to adverse events observed in non-muscle invasive bladder cancer (NMIBC) patients treated with Mycobacterium bovis BCG, alternative immunomodulators have been evaluated. Mycobacterium brumae, a safe mycobacterium with demonstrated in vitro, ex vivo and in vivo antitumor activity emerges as a promising candidate to replace BCG. Immunomodulator studies overlook older patients, despite age is associated with immunosenescence and the target population for NMIBC treatment is mainly men over 60 years old. Here we investigate the immunomodulatory capacity of BCG and M. brumae in peripheral blood mononuclear cells (PBMC) from healthy donors of various age groups together with NMIBC patients.

PBMC from young (18-35 years old) and older (60-75) healthy volunteers and NMBC patients (over 65) were stimulated with M. brumae or BCG. PBMC phenotyping was performed by flow cytometry. The direct and indirect cytotoxicity of mycobacteria-activated PBMC against bladder tumour cells and the release of a broad cytokines panel were analysed.

A significant age-dependent impact on T-cell differentiation profile was observed. The frequencies of activation-induced markers (CD69 and CD137) on CD4⁺ and CD8⁺ T cells stimulated with mycobacteria differed significantly between age groups and between healthy individuals and NMIBC patients. Diminished cytokine production (primary IL-8, IL-17, IFN-γ) in mycobacteria-activated PBMCs was observed from aged individuals, while cytotoxic activity against tumour cells were significantly reduced in NMIBC patients.

The functionality of immune system cells differs according to the intrinsic characteristics of the population group. This heterogeneity can influence the efficacy of activation by immunomodulatory mycobacteria, ultimately impacting antitumor capacity.

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