Long-Lasting, Fine-Tuned Anti-Tumor Activity of Recombinant Listeria monocytogenes Vaccine Is Controlled by Pyroptosis and Necroptosis Regulatory and Effector Molecules

Author(s)

Olagunju, Abolaji S. ; Sardinha, Andrew V. D. ; Amarante-Mendes, Gustavo P.

• Document type: Journal article
• Source: PATHOGENS; v. 13, n. 10, p. 11-pg., 2024-10-01.

Abstract

One of the main objectives of developing new anti-cancer vaccine strategies is to effectively induce CD8+ T cell-mediated anti-tumor immunity. Live recombinant vectors, notably Listeria monocytogenes, have been shown to elicit a robust in vivo CD8+ T-cell response in preclinical settings. Significantly, it has been demonstrated that Listeria induces inflammatory/immunogenic cell death mechanisms such as pyroptosis and necroptosis in immune cells that favorably control immunological responses. Therefore, we postulated that the host's response to Listeria-based vectors and the subsequent induction of CD8+ T cell-mediated immunity would be compromised by the lack of regulatory or effector molecules involved in pyroptosis or necroptosis. To test our hypothesis, we used recombinant L. monocytogenes carrying the ovalbumin gene (LM.OVA) to vaccinate wild-type (WT), caspase-1/11-/-, gsdmd-/-, ripk3-/-, and mlkl-/- C57Bl/6 mice. We performed an in vivo cytotoxicity assay to assess the efficacy of OVA-specific CD8+ T lymphocytes in eliminating target cells in wild-type and genetically deficient backgrounds. Furthermore, we evaluated the specific anti-tumor immune response in mice inoculated with the B16F0 and B16F0.OVA melanoma cell lines. Our findings demonstrated that while caspase-1/11 and GSDMD deficiencies interfere with the rapid control of LM.OVA infection, neither of the KOs seems to contribute to the early activation of OVA-specific CTL responses. In contrast, the individual deficiency of each one of these proteins positively impacts the generation of long-lasting effector CD8+ T cells. (AU)

• FAPESP's process: 21/07624-6 - Role of inflammatory cell death mediators in the modulation anti-tumor immune response by listeria monocytogenes
• Grantee: Andrew Victor Diniz Sardinha
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 21/13486-5 - Role of apoptosis regulatory molecules and DNA demethylating agents on the activation and differentiation of antigen-specific CD8+ T lymphocytes
• Grantee: João Gustavo Pessini Amarante Mendes
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/12143-7 - In vivo activation, differentiation and effector function of antigen specific target cells by CD8+ T lymphocytes: role of Caspase1, GSDMD, RIPK3 and MLKL
• Grantee: Abolaji Samson Olagunju
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 23/02577-5 - Study of the mechanisms responsible for trained immunity induced by Bacillus Calmette-Guérin (BCG) in infectious diseases and Cancer
• Grantee: Sergio Costa Oliveira
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/25395-1 - Role of RASSF9 in melanoma using the CRISPR/Cas9 system
• Grantee: João Gustavo Pessini Amarante Mendes
• Support Opportunities: Regular Research Grants