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Published on: November 28, 2019
Attenuated Salmonella secreting interleukin-21 activates T-cells and induces anti-tumor effects
Minju Han1, Eunji Kim1, Minchan Jeong1
1Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 34134, Republic of Korea.
Abstract:
The tumor microenvironment is characterized by an immunosuppressive state. Although PD-1/PD-L1 blockade therapy activates the immune system against tumors, it has limited long-term efficacy, prompting the development of combination therapies with targeted treatments to improve cancer treatment outcomes. Recent advancements have revitalized interest in using attenuated Salmonella strains as cancer therapeutics that target tumors, induce immune responses, and promote tumor cell death, although complete tumor suppression remains challenging. We aimed to induce antitumor effects by activating the suppressed immune system within the tumor microenvironment using Salmonella-mediated secretion of interleukin-21 (IL-21). We used the tumor-targeting ability of Salmonella and its flagellar type-3 secretion system (FT3SS) to induce the secretion of IL-21 into the tumor microenvironment via the flagellar system and evaluated the local immune response. We also evaluated the efficacy of combining Salmonella-mediated IL-21 delivery and anti-PD-L1 therapy in a mouse model. IL-21 secretion promoted the recruitment of CD4+ and CD8+ T cells and enhanced the expression of cytotoxicity-related molecules. Tumor-bearing mice treated with the combination therapy with anti-PD-L1 antibodies showed improved survival rates and enhanced tumor growth inhibition. This study demonstrates the tumor-targeting capability and in vivo safety of Salmonella, highlighting its potential as a powerful cancer therapy platform.
Insights
Engineered Salmonella bacteria deliver interleukin-21 (IL-21) to tumors, activating immune cells and enhancing anti-PD-L1 therapy. This combination improves survival and inhibits tumor growth, showing Salmonella
Area of Science:
- Immunology
- Microbiology
- Oncology
Background:
- The tumor microenvironment often exhibits an immunosuppressive state, limiting the effectiveness of therapies like PD-1/PD-L1 blockade.
- Attenuated Salmonella strains are being explored as cancer therapeutics due to their tumor-targeting and immune-stimulating properties.
Purpose of the Study:
- To investigate the potential of Salmonella-mediated interleukin-21 (IL-21) delivery to activate the suppressed immune system within the tumor microenvironment.
- To evaluate the efficacy of combining Salmonella-mediated IL-21 delivery with anti-PD-L1 therapy in a preclinical cancer model.
Main Methods:
- Utilized the tumor-targeting and flagellar type-3 secretion system (FT3SS) of Salmonella to deliver IL-21 into the tumor microenvironment.
- Assessed the local immune response, including T cell recruitment and cytotoxicity marker expression.
- Evaluated the combined therapeutic effect of Salmonella-mediated IL-21 and anti-PD-L1 antibodies in a mouse model of cancer.
Main Results:
- Salmonella-mediated IL-21 secretion led to increased recruitment of CD4+ and CD8+ T cells.
- Enhanced expression of cytotoxicity-related molecules was observed in the tumor microenvironment.
- Combination therapy significantly improved survival rates and inhibited tumor growth in tumor-bearing mice.
Conclusions:
- Salmonella can be engineered to deliver therapeutic payloads like IL-21 directly to tumors.
- The combination of Salmonella-mediated IL-21 and anti-PD-L1 therapy demonstrates potent antitumor effects.
- Salmonella presents a promising platform for developing novel cancer immunotherapies.
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