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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 previously reported that transient engineering of tumor-specific CD8 T cells with IL-12 mRNA enhanced their systemic therapeutic efficacy when delivered intratumorally. Here, we mix T cells enginee...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10040457/ https://www.ncbi.nlm.nih.gov/pubmed/36933554 http://dx.doi.org/10.1016/j.xcrm.2023.100978 |
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author | Olivera, Irene Bolaños, Elixabet Gonzalez-Gomariz, Jose Hervas-Stubbs, Sandra Mariño, Karina V. Luri-Rey, Carlos Etxeberria, Iñaki Cirella, Assunta Egea, Josune Glez-Vaz, Javier Garasa, Saray Alvarez, Maite Eguren-Santamaria, Iñaki Guedan, Sonia Sanmamed, Miguel F. Berraondo, Pedro Rabinovich, Gabriel A. Teijeira, Alvaro Melero, Ignacio |
author_facet | Olivera, Irene Bolaños, Elixabet Gonzalez-Gomariz, Jose Hervas-Stubbs, Sandra Mariño, Karina V. Luri-Rey, Carlos Etxeberria, Iñaki Cirella, Assunta Egea, Josune Glez-Vaz, Javier Garasa, Saray Alvarez, Maite Eguren-Santamaria, Iñaki Guedan, Sonia Sanmamed, Miguel F. Berraondo, Pedro Rabinovich, Gabriel A. Teijeira, Alvaro Melero, Ignacio |
author_sort | Olivera, Irene |
collection | PubMed |
description | Interleukin-12 (IL-12) gene transfer enhances the therapeutic potency of adoptive T cell therapies. We previously reported that transient engineering of tumor-specific CD8 T cells with IL-12 mRNA enhanced their systemic therapeutic efficacy when delivered intratumorally. Here, we mix T cells engineered with mRNAs to express 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 injected 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 recapitulated in cultures of tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells on IL-12 and DRIL18 mRNA electroporation. |
format | Online Article Text |
id | pubmed-10040457 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-100404572023-03-28 mRNAs encoding IL-12 and a decoy-resistant variant of IL-18 synergize to engineer T cells for efficacious intratumoral adoptive immunotherapy Olivera, Irene Bolaños, Elixabet Gonzalez-Gomariz, Jose Hervas-Stubbs, Sandra Mariño, Karina V. Luri-Rey, Carlos Etxeberria, Iñaki Cirella, Assunta Egea, Josune Glez-Vaz, Javier Garasa, Saray Alvarez, Maite Eguren-Santamaria, Iñaki Guedan, Sonia Sanmamed, Miguel F. Berraondo, Pedro Rabinovich, Gabriel A. Teijeira, Alvaro Melero, Ignacio Cell Rep Med Article Interleukin-12 (IL-12) gene transfer enhances the therapeutic potency of adoptive T cell therapies. We previously reported that transient engineering of tumor-specific CD8 T cells with IL-12 mRNA enhanced their systemic therapeutic efficacy when delivered intratumorally. Here, we mix T cells engineered with mRNAs to express 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 injected 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 recapitulated in cultures of tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells on IL-12 and DRIL18 mRNA electroporation. Elsevier 2023-03-17 /pmc/articles/PMC10040457/ /pubmed/36933554 http://dx.doi.org/10.1016/j.xcrm.2023.100978 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Olivera, Irene Bolaños, Elixabet Gonzalez-Gomariz, Jose Hervas-Stubbs, Sandra Mariño, Karina V. Luri-Rey, Carlos Etxeberria, Iñaki Cirella, Assunta Egea, Josune Glez-Vaz, Javier Garasa, Saray Alvarez, Maite Eguren-Santamaria, Iñaki Guedan, Sonia Sanmamed, Miguel F. Berraondo, Pedro Rabinovich, Gabriel A. Teijeira, Alvaro Melero, Ignacio mRNAs encoding IL-12 and a decoy-resistant variant of IL-18 synergize to engineer T cells for efficacious intratumoral adoptive immunotherapy |
title | mRNAs encoding IL-12 and a decoy-resistant variant of IL-18 synergize to engineer T cells for efficacious intratumoral adoptive immunotherapy |
title_full | mRNAs encoding IL-12 and a decoy-resistant variant of IL-18 synergize to engineer T cells for efficacious intratumoral adoptive immunotherapy |
title_fullStr | mRNAs encoding IL-12 and a decoy-resistant variant of IL-18 synergize to engineer T cells for efficacious intratumoral adoptive immunotherapy |
title_full_unstemmed | mRNAs encoding IL-12 and a decoy-resistant variant of IL-18 synergize to engineer T cells for efficacious intratumoral adoptive immunotherapy |
title_short | mRNAs encoding IL-12 and a decoy-resistant variant of IL-18 synergize to engineer T cells for efficacious intratumoral adoptive immunotherapy |
title_sort | mrnas encoding il-12 and a decoy-resistant variant of il-18 synergize to engineer t cells for efficacious intratumoral adoptive immunotherapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10040457/ https://www.ncbi.nlm.nih.gov/pubmed/36933554 http://dx.doi.org/10.1016/j.xcrm.2023.100978 |
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