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Updated: Jun 21, 2025
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Attenuated mutants of Salmonella enterica Typhimurium mediate melanoma regression via an immune response
Genesy Pérez Jorge1,2, Marco Gontijo1,3, Marina Flóro E Silva1,4
1Departamento de Genética, Evolução, Microbiologia e Immunologia, Instituto de Biologia, Universidade Estadual de Campinas-UNICAMP, Campinas, SP, Brazil.
Abstract:
The lack of effective treatment options for an increasing number of cancer cases highlights the need for new anticancer therapeutic strategies. Immunotherapy mediated by Salmonella enterica Typhimurium is a promising anticancer treatment. Candidate strains for anticancer therapy must be attenuated while retaining their antitumor activity. Here, we investigated the attenuation and antitumor efficacy of two S. enterica Typhimurium mutants, ΔtolRA and ΔihfABpmi, in a murine melanoma model. Results showed high attenuation of ΔtolRA in the Galleria mellonella model, and invasion and survival in tumor cells. However, it showed weak antitumor effects in vitro and in vivo. Contrastingly, lower attenuation of the attenuated ΔihfABpmi strain resulted in regression of tumor mass in all mice, approximately 6 days after the first treatment. The therapeutic response induced by ΔihfABpmi was accompanied with macrophage accumulation of antitumor phenotype (M1) and significant increase in the mRNAs of proinflammatory mediators (TNF-α, IL-6, and iNOS) and an apoptosis inducer (Bax). Our findings indicate that the attenuated ΔihfABpmi exerts its antitumor activity by inducing macrophage infiltration or reprogramming the immunosuppressed tumor microenvironment to an activated state, suggesting that attenuated S. enterica Typhimurium strains based on nucleoid-associated protein genes deletion could be immunotherapeutic against cancer.
Insights
Salmonella enterica Typhimurium mutants show promise as cancer immunotherapies. The attenuated ΔihfABpmi strain effectively reduced melanoma tumors by activating antitumor immune responses.
Area of Science:
- Oncology
- Microbiology
- Immunology
Background:
- Rising cancer incidence necessitates novel therapeutic strategies.
- Salmonella enterica Typhimurium immunotherapy presents a promising anticancer approach.
- Attenuated bacterial strains are crucial for safe and effective cancer therapy.
Purpose of the Study:
- To evaluate the attenuation and antitumor efficacy of two S. enterica Typhimurium mutants (ΔtolRA and ΔihfABpmi).
- To investigate the therapeutic potential of these mutants in a murine melanoma model.
Main Methods:
- Assessment of bacterial attenuation using Galleria mellonella model.
- Evaluation of bacterial invasion and survival in tumor cells.
- In vitro and in vivo antitumor activity testing in a murine melanoma model.
- Analysis of immune cell profiles (macrophage polarization) and gene expression of inflammatory mediators and apoptosis markers.
Main Results:
- The ΔtolRA mutant exhibited high attenuation but weak antitumor effects.
- The attenuated ΔihfABpmi strain demonstrated significant tumor regression in mice within 6 days.
- ΔihfABpmi treatment led to M1 macrophage accumulation and increased expression of TNF-α, IL-6, iNOS, and Bax.
Conclusions:
- Attenuated S. enterica Typhimurium strains, particularly ΔihfABpmi, can effectively treat cancer.
- The antitumor activity is mediated by reprogramming the tumor microenvironment towards an activated immune state, involving macrophage infiltration.
- Targeting nucleoid-associated protein genes offers a viable strategy for developing Salmonella-based cancer immunotherapies.
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