title: An Oral Salmonella-Based Vaccine Inhibits Liver Metastases by Promoting Tumor-Specific T-Cell-Mediated Immunity in Celiac and Portal Lymph Nodes: A Preclinical Study.
abstract: Primary tumor excision is one of the most widely used therapies of cancer. However, the risk of metastases development still exists following tumor resection. The liver is a common site of metastatic disease for numerous cancers. Breast cancer is one of the most frequent sources of metastases to the liver. The aim of this work was to evaluate the efficacy of the orally administered Salmonella Typhi vaccine strain CVD 915 on the development of liver metastases in a mouse model of breast cancer. To this end, one group of BALB/c mice was orogastrically immunized with CVD 915, while another received PBS as a control. After 24 h, mice were injected with LM3 mammary adenocarcinoma cells into the spleen and subjected to splenectomy. This oral Salmonella-based vaccine produced an antitumor effect, leading to a decrease in the number and volume of liver metastases. Immunization with Salmonella induced an early cellular immune response in mice. This innate stimulation rendered a large production of IFN-γ by intrahepatic immune cells (IHIC) detected within 24 h. An antitumor adaptive immunity was found in the liver and celiac and portal lymph nodes (LDLN) 21 days after oral bacterial inoculation. The antitumor immune response inside the liver was associated with increased CD4(+) and dendritic cell populations as well as with an inflammatory infiltrate located around liver metastatic nodules. Enlarged levels of inflammatory cytokines (IFN-γ and TNF) were also detected in IHIC. Furthermore, a tumor-specific production of IFN-γ and TNF as well as tumor-specific IFN-γ-producing CD8 T cells (CD8(+)IFN-γ(+)) were found in the celiac and portal lymph nodes of Salmonella-treated mice. This study provides first evidence for the involvement of LDLN in the development of an efficient cellular immune response against hepatic tumors, which resulted in the elimination of liver metastases after oral Salmonella-based vaccination.
authors.affiliation: Centro de Estudios Farmacológicos y Botánicos-Consejo Nacional de Investigaciones Científicas y Técnicas (CEFyBO-CONICET), Facultad de Medicina, Universidad de Buenos Aires , Buenos Aires , Argentina.
authors.forename: Alejandrina
authors.initials: A
authors.lastname: Vendrell
authors.affiliation: Centro de Estudios Farmacológicos y Botánicos-Consejo Nacional de Investigaciones Científicas y Técnicas (CEFyBO-CONICET), Facultad de Medicina, Universidad de Buenos Aires , Buenos Aires , Argentina.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mongini
authors.affiliation: Instituto de Biotecnología, Instituto Nacional de Tecnología Agropecuaria (INTA) , Buenos Aires , Argentina.
authors.forename: María José
authors.initials: MJ
authors.lastname: Gravisaco
authors.affiliation: Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni (IDEHU). Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires , Buenos Aires , Argentina.
authors.forename: Andrea
authors.initials: A
authors.lastname: Canellada
authors.affiliation: Centro de Estudios Farmacológicos y Botánicos-Consejo Nacional de Investigaciones Científicas y Técnicas (CEFyBO-CONICET), Facultad de Medicina, Universidad de Buenos Aires , Buenos Aires , Argentina.
authors.forename: Agustina Inés
authors.initials: AI
authors.lastname: Tesone
authors.affiliation: Centro de Estudios Farmacológicos y Botánicos-Consejo Nacional de Investigaciones Científicas y Técnicas (CEFyBO-CONICET), Facultad de Medicina, Universidad de Buenos Aires , Buenos Aires , Argentina.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Goin
authors.affiliation: Centro de Estudios Farmacológicos y Botánicos-Consejo Nacional de Investigaciones Científicas y Técnicas (CEFyBO-CONICET), Facultad de Medicina, Universidad de Buenos Aires , Buenos Aires , Argentina.
authors.forename: Claudia Inés
authors.initials: CI
authors.lastname: Waldner
keywords: Salmonella Typhi; Th1 immune response; antitumor CD8+ T cells; breast cancer; celiac and portal lymph nodes; liver metastases; vaccine