Inflammasome activation, NLRP3 engagement and macrophage recruitment to tumor microenvironment are all required for Salmonella antitumor effect.

Abstract

Salmonella-based cancer therapies show great potential in preclinical models, but for most cases the observed antitumor effect is transient. Understanding the basis of the antitumor efficacy might guide the design of improved strains that elicit long-lasting effects, paving the wave for clinical use.  Here, we deepened into the role of macrophages and inflammasome activation in the context of Salmonella anti-melanoma effect. We showed inflammasome activation in melanoma cells upon infection, which correlated with cell surface exposure of gasdermin-D (GSDM-D) and calreticulin (CRT) and High mobility group box 1 protein (HMGB-1) release, suggesting immunogenic cell death, particularly pyroptosis. Salmonella infection upregulated levels of Caspase-11 (Casp11) mRNA, but not Nlrp3 or Nlrc4 mRNA, the only described inflammasome receptors engaged by Salmonella, suggesting that non-canonical inflammasome activation could be occurring in melanoma cells. Intratumoral administration of Salmonella to melanoma-bearing mice elicited local inflammasome activation and interleukin-1β (IL-1β) production together with tumor growth retardation and extended survival in wild type but not Caspase-1/11 (Casp1/11) knockout mice despite similar levels of intratumoral IL-1β in the later. Salmonella antitumor activity was also suppressed in melanoma bearing Nlrp3 knockout mice. Salmonella induced macrophage recruitment to the tumor site and infiltrating cells exhibited inflammasome activation. Depletion experiments confirmed that macrophages are also essential for Salmonella anti-melanoma effect. Intratumoral macrophages showed a marked M2/M1 shift soon after treatment but this inflammatory profile is then lost, which could explain the transient effect of therapy.  All in all, our results highlight CASP-1/11 axis and macrophages as essential players in Salmonella-based cancer immunotherapy and suggest a possible target for future interventions.

• Authors: Amy Mónaco, Sofía Chilibroste, Lucía Yim, Jose Alejandro Chabalgoity, María Moreno
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 71 Issue 9 Pg. 2141-2150 (Sep 2022) ISSN: 1432-0851 [Electronic] Germany
• PMID: 35061085 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• Inflammasomes
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• RNA, Messenger
• Caspase 1

Topics

• Animals
• Caspase 1 (metabolism)
• Inflammasomes (immunology)
• Interleukin-1beta (metabolism)
• Macrophages (immunology)
• Mice
• Mice, Inbred C57BL
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics)
• Neoplasms (immunology, therapy)
• RNA, Messenger (metabolism)
• Salmonella
• Tumor Microenvironment