Attenuated mutants of Salmonella enterica Typhimurium mediate melanoma regression via an immune response

Author(s)

Jorge, Genesy Perez ; Gontijo, Marco ; Floro e Silva, Marina ; Goes, Isabella Carolina Rodrigues Dos Santos ; Jaimes-Florez, Yessica Paola ; Coser, Lilian de Oliveira ; Rocha, Francisca Janaina Soares ; Giorgio, Selma ; Brocchi, Marcelo

• Document type: Journal article
• Source: Experimental Biology and Medicine; v. 249, p. 19-pg., 2024-06-21.

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, Delta tolRA and Delta ihfABpmi, in a murine melanoma model. Results showed high attenuation of Delta tolRA 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 Delta ihfABpmi strain resulted in regression of tumor mass in all mice, approximately 6 days after the first treatment. The therapeutic response induced by Delta ihfABpmi was accompanied with macrophage accumulation of antitumor phenotype (M1) and significant increase in the mRNAs of proinflammatory mediators (TNF-alpha, IL-6, and iNOS) and an apoptosis inducer (Bax). Our findings indicate that the attenuated Delta ihfABpmi 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. (AU)

• FAPESP's process: 19/17091-5 - Phenotypic analysis of macrophages and histopathology in mice infected with Leishmania braziliensis
• Grantee: Marina Flóro e Silva
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 21/10577-0 - Biology of Bacteria and Bacteriophages Research Center
• Grantee: Shaker Chuck Farah
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 21/00465-0 - Genomic, pathogenicity, resistance, antitumoral therapy and vaccines development based on Salmonella enterica
• Grantee: Marcelo Brocchi
• Support Opportunities: Regular Research Grants
• FAPESP's process: 22/11399-0 - Salmonella enterica and Outer Membrane Vesicles as Antitumor Agents
• Grantee: Genesy Perez Jorge
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
• FAPESP's process: 20/01535-9 - Comparative genomics and antimicrobial activity of recombinant phage endolisins against multi-resistant gram-negative bacteria
• Grantee: Marco Túlio Pardini Gontijo
• Support Opportunities: Scholarships in Brazil - Master