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Int J Cancer ; 155(2): 352-364, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38483404

RESUMEN

Treatment for higher-risk non-muscle invasive bladder cancer (NMIBC) involves intravesical immunotherapy with Bacillus Calmette Guérin (BCG); however, disease recurrence and progression occur frequently. Systemic immunity is critical for successful cancer immunotherapy; thus, recurrence of NMIBC may be due to suboptimal systemic activation of anti-tumor immunity after local immunotherapy. We previously reported that systemically acquired trained immunity (a form of innate immune memory) in circulating monocytes is associated with increased time-to-recurrence in patients with NMIBC treated with BCG. Herein, we used a mouse model of NMIBC to compare the effects of intravesical versus intravenous (systemic) BCG immunotherapy on the local and peripheral immune microenvironments. We also assessed whether BCG-induced trained immunity modulates anti-tumor immune responses. Compared with intravesical BCG, which led to a tumor-promoting immune microenvironment, intravenous BCG resulted in an anti-tumoral bladder microenvironment characterized by increased proportions of cytotoxic T lymphocytes (CTLs), and decreased proportions of myeloid-derived suppressor cells. Polarization toward anti-tumoral immunity occurred in draining lymph nodes, spleen, and bone marrow following intravenous versus intravesical BCG treatment. Pre-treatment with intravesical BCG was associated with increased rate of tumor growth compared with intravenous BCG pre-treatment. Trained immunity contributed to remodeling of the tumor immune microenvironment, as co-instillation of BCG-trained macrophages with ovalbumin-expressing bladder tumor cells increased the proportion of tumor-specific CTLs. Furthermore, BCG-trained dendritic cells exhibited enhanced antigen uptake and presentation and promoted CTL proliferation. Our data support the concept that systemic immune activation promotes anti-tumor responses, and that BCG-induced trained immunity is important in driving anti-tumor adaptive immunity.


Asunto(s)
Vacuna BCG , Inmunoterapia , Microambiente Tumoral , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/terapia , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Animales , Microambiente Tumoral/inmunología , Ratones , Vacuna BCG/inmunología , Vacuna BCG/administración & dosificación , Vacuna BCG/uso terapéutico , Inmunoterapia/métodos , Femenino , Administración Intravesical , Ratones Endogámicos C57BL , Linfocitos T Citotóxicos/inmunología , Humanos , Modelos Animales de Enfermedad , Inmunidad Innata/inmunología , Línea Celular Tumoral , Memoria Inmunológica/inmunología , Células Supresoras de Origen Mieloide/inmunología , Inmunidad Entrenada
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