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

Autor(es)

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

• Tipo de documento: Artigo Científico
• Fonte: PATHOGENS; v. 13, n. 10, p. 11-pg., 2024-10-01.

Resumo

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)

• Processo FAPESP: 21/07624-6 - Papel dos mediadores de morte celular inflamatória na modulação da resposta imune anti-tumoral por Listeria monocytogenes
• Beneficiário: Andrew Victor Diniz Sardinha
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 21/13486-5 - Papel de moléculas reguladoras da apoptose e de agentes desmetilantes de DNA na ativação e diferenciação de linfócitos T CD8
• Beneficiário: João Gustavo Pessini Amarante Mendes
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 21/12143-7 - Ativação in vivo, diferenciação e função efetora de células alvo específicas do antígeno por linfócitos T CD8+: papel da Caspase1, GSDMD, RIPK3 e MLKL
• Beneficiário: Abolaji Samson Olagunju
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 23/02577-5 - Estudo dos mecanismos responsáveis pela imunidade treinada induzida pelo Bacillus Calmette-Guérin (BCG) em doenças infecciosas e Câncer
• Beneficiário: Sergio Costa Oliveira
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 18/25395-1 - Avaliação do papel de RASSF9 em melanoma através do sistema CRISPR/Cas9
• Beneficiário: João Gustavo Pessini Amarante Mendes
• Modalidade de apoio: Auxílio à Pesquisa - Regular