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OX40L-expressing recombinant modified vaccinia virus Ankara induces potent antitumor immunity via reprogramming Tregs

Effective depletion of immune suppressive regulatory T cells (Tregs) in the tumor microenvironment without triggering systemic autoimmunity is an important strategy for cancer immunotherapy. Modified vaccinia virus Ankara (MVA) is a highly attenuated, non-replicative vaccinia virus with a long histo...

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Autores principales: Yang, Ning, Wang, Yi, Liu, Shuaitong, Tariq, Shanza Baseer, Luna, Joseph M., Mazo, Gregory, Tan, Adrian, Zhang, Tuo, Wang, Jiahu, Yan, Wei, Choi, John, Rossi, Anthony, Xiang, Jenny Zhaoying, Rice, Charles M., Merghoub, Taha, Wolchok, Jedd D., Deng, Liang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165539/
https://www.ncbi.nlm.nih.gov/pubmed/37145142
http://dx.doi.org/10.1084/jem.20221166
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author Yang, Ning
Wang, Yi
Liu, Shuaitong
Tariq, Shanza Baseer
Luna, Joseph M.
Mazo, Gregory
Tan, Adrian
Zhang, Tuo
Wang, Jiahu
Yan, Wei
Choi, John
Rossi, Anthony
Xiang, Jenny Zhaoying
Rice, Charles M.
Merghoub, Taha
Wolchok, Jedd D.
Deng, Liang
author_facet Yang, Ning
Wang, Yi
Liu, Shuaitong
Tariq, Shanza Baseer
Luna, Joseph M.
Mazo, Gregory
Tan, Adrian
Zhang, Tuo
Wang, Jiahu
Yan, Wei
Choi, John
Rossi, Anthony
Xiang, Jenny Zhaoying
Rice, Charles M.
Merghoub, Taha
Wolchok, Jedd D.
Deng, Liang
author_sort Yang, Ning
collection PubMed
description Effective depletion of immune suppressive regulatory T cells (Tregs) in the tumor microenvironment without triggering systemic autoimmunity is an important strategy for cancer immunotherapy. Modified vaccinia virus Ankara (MVA) is a highly attenuated, non-replicative vaccinia virus with a long history of human use. Here, we report rational engineering of an immune-activating recombinant MVA (rMVA, MVA∆E5R-Flt3L-OX40L) with deletion of the vaccinia E5R gene (encoding an inhibitor of the DNA sensor cyclic GMP-AMP synthase, cGAS) and expression of two membrane-anchored transgenes, Flt3L and OX40L. Intratumoral (IT) delivery of rMVA (MVA∆E5R-Flt3L-OX40L) generates potent antitumor immunity, dependent on CD8(+) T cells, the cGAS/STING-mediated cytosolic DNA-sensing pathway, and type I IFN signaling. Remarkably, IT rMVA (MVA∆E5R-Flt3L-OX40L) depletes OX40(hi) regulatory T cells via OX40L/OX40 interaction and IFNAR signaling. Single-cell RNA-seq analyses of tumors treated with rMVA showed the depletion of OX40(hi)CCR8(hi) Tregs and expansion of IFN-responsive Tregs. Taken together, our study provides a proof-of-concept for depleting and reprogramming intratumoral Tregs via an immune-activating rMVA.
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spelling pubmed-101655392023-11-05 OX40L-expressing recombinant modified vaccinia virus Ankara induces potent antitumor immunity via reprogramming Tregs Yang, Ning Wang, Yi Liu, Shuaitong Tariq, Shanza Baseer Luna, Joseph M. Mazo, Gregory Tan, Adrian Zhang, Tuo Wang, Jiahu Yan, Wei Choi, John Rossi, Anthony Xiang, Jenny Zhaoying Rice, Charles M. Merghoub, Taha Wolchok, Jedd D. Deng, Liang J Exp Med Article Effective depletion of immune suppressive regulatory T cells (Tregs) in the tumor microenvironment without triggering systemic autoimmunity is an important strategy for cancer immunotherapy. Modified vaccinia virus Ankara (MVA) is a highly attenuated, non-replicative vaccinia virus with a long history of human use. Here, we report rational engineering of an immune-activating recombinant MVA (rMVA, MVA∆E5R-Flt3L-OX40L) with deletion of the vaccinia E5R gene (encoding an inhibitor of the DNA sensor cyclic GMP-AMP synthase, cGAS) and expression of two membrane-anchored transgenes, Flt3L and OX40L. Intratumoral (IT) delivery of rMVA (MVA∆E5R-Flt3L-OX40L) generates potent antitumor immunity, dependent on CD8(+) T cells, the cGAS/STING-mediated cytosolic DNA-sensing pathway, and type I IFN signaling. Remarkably, IT rMVA (MVA∆E5R-Flt3L-OX40L) depletes OX40(hi) regulatory T cells via OX40L/OX40 interaction and IFNAR signaling. Single-cell RNA-seq analyses of tumors treated with rMVA showed the depletion of OX40(hi)CCR8(hi) Tregs and expansion of IFN-responsive Tregs. Taken together, our study provides a proof-of-concept for depleting and reprogramming intratumoral Tregs via an immune-activating rMVA. Rockefeller University Press 2023-05-05 /pmc/articles/PMC10165539/ /pubmed/37145142 http://dx.doi.org/10.1084/jem.20221166 Text en © 2023 Yang et al. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Yang, Ning
Wang, Yi
Liu, Shuaitong
Tariq, Shanza Baseer
Luna, Joseph M.
Mazo, Gregory
Tan, Adrian
Zhang, Tuo
Wang, Jiahu
Yan, Wei
Choi, John
Rossi, Anthony
Xiang, Jenny Zhaoying
Rice, Charles M.
Merghoub, Taha
Wolchok, Jedd D.
Deng, Liang
OX40L-expressing recombinant modified vaccinia virus Ankara induces potent antitumor immunity via reprogramming Tregs
title OX40L-expressing recombinant modified vaccinia virus Ankara induces potent antitumor immunity via reprogramming Tregs
title_full OX40L-expressing recombinant modified vaccinia virus Ankara induces potent antitumor immunity via reprogramming Tregs
title_fullStr OX40L-expressing recombinant modified vaccinia virus Ankara induces potent antitumor immunity via reprogramming Tregs
title_full_unstemmed OX40L-expressing recombinant modified vaccinia virus Ankara induces potent antitumor immunity via reprogramming Tregs
title_short OX40L-expressing recombinant modified vaccinia virus Ankara induces potent antitumor immunity via reprogramming Tregs
title_sort ox40l-expressing recombinant modified vaccinia virus ankara induces potent antitumor immunity via reprogramming tregs
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165539/
https://www.ncbi.nlm.nih.gov/pubmed/37145142
http://dx.doi.org/10.1084/jem.20221166
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