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.
Highlights
The development of novel cancer treatments is a major subject of study around the globe
Intrahepatic immune cells, mesenteric lymph nodes (MLN), and liver-draining lymph nodes (LDLN) cells obtained from BALB/c mice were cultured at 37°C in a humidified 5% CO2 environment in RPMI supplemented with 2 mM glutamine, 25 mM HEPES, 0.05 mM 2-mercaptoethanol, 100 U/ml penicillin, 100 μg/ml streptomycin, and 10% heat-inactivated fetal calf serum (FCS)
Breaking the hepatic tolerance and counteracting the immunosuppressive mechanisms induced by cancer cells within the liver are required to induce an effective immune response against liver cancer
Summary
The development of novel cancer treatments is a major subject of study around the globe. More than 90% of cancer-related deaths are due to metastatic disease and not from the primary tumors from which they arise [1]. Excision of primary tumors is one of the most widely used cancer treatments. The risk of metastases development still exists following tumor resection [2]. Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related death in women worldwide. Most deaths from breast cancer are from metastatic disease [3]. The liver is a common site of metastatic disease for numerous types of cancer. Colon, pancreatic, mammary, and gastric adenocarcinomas are the most frequent types of carcinoma to metastasize to the liver [4]
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