mRNAs encoding IL-12 and a decoy-resistant variant of IL-18 synergize to engineer T cells for efficacious intratumoral adoptive immunotherapy

Interleukin-12 (IL-12) gene transfer enhances the therapeutic potency of adoptive T cell therapies. We previ-ously reported that transient engineering of tumor-specific CD8 T cells with IL-12 mRNA enhanced their sys-temic therapeutic efficacy when delivered intratumorally. Here, we mix T cells engin...

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Detalhes bibliográficos
Autores: Olivera-Valle, I. (Irene)|||/items/c3d06db0-d277-4fe8-9b33-59005441fec1, Bolaños-Mateo, E. (Elixabet)|||/items/073a1977-5579-4bd1-8604-98b3ccfd4361, González-Gomariz, J. (José)|||/items/99ec6fe7-0d9d-4d48-938e-6bec841670af, Hervas-Stubbs, S. (Sandra)|||/items/8f56cb52-4465-4428-8acf-e50439c6be8f, Mariño, K. (Karina)|||/items/3881e443-7d39-4161-a1cc-f00612ae60d5, Luri-Rey, C. (Carlos)|||/items/efa6fd23-1164-4af9-8456-9c8fa4fddb8d, Etxeberria, I. (Iñaki)|||/items/73830f45-c05b-49ed-a21a-f7cbacfc8f07, Cirella, A. (Assunta)|||/items/398b3896-8ce3-4831-8ebc-1d86487cd790, Egea, J. (Josune)|||/items/cc45fa4c-fcd3-4e45-be85-9d3d5de9a2b7, González-Vaz, J. (Javier)|||/items/9d321bb0-f713-4608-8d35-15b1c9588b76, Garasa, S. (Saray)|||/items/51924af8-57aa-477c-b3d8-886422be3713, Álvarez-Rodríguez, M. (Maite)|||/items/e298edcf-2e7f-4001-a5e2-244efa1a7781, Eguren-Santamaría, I. (Iñaki)|||/items/a597d707-9f63-46ab-8da1-e99ed05e644e, Guedan, S. (Sonia)|||/items/2ede3788-adc3-4da4-a72e-8b690cf08dee, Fernández-de-Sanmamed-Gutiérrez, M. (Miguel)|||/items/35ac602c-f0ff-4664-bbd2-506afc96db09, Berraondo-López, P. (Pedro)|||/items/b1f8ccc3-8e08-4ece-967c-64ccfc0e5b91, Rabinovich, G.A. (Gabriel A.)|||/items/189639ec-d2b3-498b-9e4c-9caf6819fafd, Teijeira-Sánchez, A. (Álvaro)|||/items/8a954ec4-8458-46ea-b8e6-3165119bef30, Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4e
Formato: artículo
Fecha de publicación:2023
País:España
Recursos:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/67279
Acesso em linha:https://hdl.handle.net/10171/67279
Access Level:acceso abierto
Palavra-chave:Protein
Tumor-Infiltrating lymphocytes
Dendritic cells
E-Selectin
Therapy
Effector
Cancer
Interleukin-12
Responses
Immunity
Descrição
Resumo:Interleukin-12 (IL-12) gene transfer enhances the therapeutic potency of adoptive T cell therapies. We previ-ously reported that transient engineering of tumor-specific CD8 T cells with IL-12 mRNA enhanced their sys-temic therapeutic efficacy when delivered intratumorally. Here, we mix T cells engineered with mRNAs to ex-press either single-chain IL-12 (scIL-12) or an IL-18 decoy-resistant variant (DRIL18) that is not functionally hampered by IL-18 binding protein (IL-18BP). These mRNA-engineered T cell mixtures are repeatedly in-jected into mouse tumors. Pmel-1 T cell receptor (TCR)-transgenic T cells electroporated with scIL-12 or DRIL18 mRNAs exert powerful therapeutic effects in local and distant melanoma lesions. These effects are associated with T cell metabolic fitness, enhanced miR-155 control on immunosuppressive target genes, enhanced expression of various cytokines, and changes in the glycosylation profile of surface proteins, enabling adhesiveness to E-selectin. Efficacy of this intratumoral immunotherapeutic strategy is recapitu-lated in cultures of tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells on IL -12 and DRIL18 mRNA electroporation.

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