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RIG-I activating immunostimulatory RNA boosts the efficacy of anticancer vaccines and synergizes with immune checkpoint blockade

BACKGROUND: Antibody-mediated targeting of regulatory T cell receptors such as CTLA-4 enhances antitumor immune responses against several cancer entities including malignant melanoma. Yet, therapeutic success in patients remains variable underscoring the need for novel combinatorial approaches. METH...

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Autores principales: Heidegger, Simon, Kreppel, Diana, Bscheider, Michael, Stritzke, Florian, Nedelko, Tatiana, Wintges, Alexander, Bek, Sarah, Fischer, Julius C., Graalmann, Theresa, Kalinke, Ulrich, Bassermann, Florian, Haas, Tobias, Poeck, Hendrik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444128/
https://www.ncbi.nlm.nih.gov/pubmed/30852164
http://dx.doi.org/10.1016/j.ebiom.2019.02.056
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author Heidegger, Simon
Kreppel, Diana
Bscheider, Michael
Stritzke, Florian
Nedelko, Tatiana
Wintges, Alexander
Bek, Sarah
Fischer, Julius C.
Graalmann, Theresa
Kalinke, Ulrich
Bassermann, Florian
Haas, Tobias
Poeck, Hendrik
author_facet Heidegger, Simon
Kreppel, Diana
Bscheider, Michael
Stritzke, Florian
Nedelko, Tatiana
Wintges, Alexander
Bek, Sarah
Fischer, Julius C.
Graalmann, Theresa
Kalinke, Ulrich
Bassermann, Florian
Haas, Tobias
Poeck, Hendrik
author_sort Heidegger, Simon
collection PubMed
description BACKGROUND: Antibody-mediated targeting of regulatory T cell receptors such as CTLA-4 enhances antitumor immune responses against several cancer entities including malignant melanoma. Yet, therapeutic success in patients remains variable underscoring the need for novel combinatorial approaches. METHODS: Here we established a vaccination strategy that combines engagement of the nucleic acid-sensing pattern recognition receptor RIG-I, antigen and CTLA-4 blockade. We used in vitro transcribed 5′-triphosphorylated RNA (3pRNA) to therapeutically target the RIG-I pathway. We performed in vitro functional analysis in bone-marrow derived dendritic cells and investigated RIG-I-enhanced vaccines in different murine melanoma models. FINDINGS: We found that protein vaccination together with RIG-I ligation via 3pRNA strongly synergizes with CTLA-4 blockade to induce expansion and activation of antigen-specific CD8(+) T cells that translates into potent antitumor immunity. RIG-I-induced cross-priming of cytotoxic T cells as well as antitumor immunity were dependent on the host adapter protein MAVS and type I interferon (IFN-I) signaling and were mediated by dendritic cells. INTERPRETATION: Overall, our data demonstrate the potency of a novel combinatorial vaccination strategy combining RIG-I-driven immunization with CTLA-4 blockade to prevent and treat experimental melanoma. FUND: German Research Foundation (SFB 1335, SFB 1371), EMBO, Else Kröner-Fresenius-Foundation, German Cancer Aid, European Hematology Association, DKMS Foundation for Giving Life, Dres. Carl Maximilian and Carl Manfred Bayer-Foundation.
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spelling pubmed-64441282019-04-12 RIG-I activating immunostimulatory RNA boosts the efficacy of anticancer vaccines and synergizes with immune checkpoint blockade Heidegger, Simon Kreppel, Diana Bscheider, Michael Stritzke, Florian Nedelko, Tatiana Wintges, Alexander Bek, Sarah Fischer, Julius C. Graalmann, Theresa Kalinke, Ulrich Bassermann, Florian Haas, Tobias Poeck, Hendrik EBioMedicine Research paper BACKGROUND: Antibody-mediated targeting of regulatory T cell receptors such as CTLA-4 enhances antitumor immune responses against several cancer entities including malignant melanoma. Yet, therapeutic success in patients remains variable underscoring the need for novel combinatorial approaches. METHODS: Here we established a vaccination strategy that combines engagement of the nucleic acid-sensing pattern recognition receptor RIG-I, antigen and CTLA-4 blockade. We used in vitro transcribed 5′-triphosphorylated RNA (3pRNA) to therapeutically target the RIG-I pathway. We performed in vitro functional analysis in bone-marrow derived dendritic cells and investigated RIG-I-enhanced vaccines in different murine melanoma models. FINDINGS: We found that protein vaccination together with RIG-I ligation via 3pRNA strongly synergizes with CTLA-4 blockade to induce expansion and activation of antigen-specific CD8(+) T cells that translates into potent antitumor immunity. RIG-I-induced cross-priming of cytotoxic T cells as well as antitumor immunity were dependent on the host adapter protein MAVS and type I interferon (IFN-I) signaling and were mediated by dendritic cells. INTERPRETATION: Overall, our data demonstrate the potency of a novel combinatorial vaccination strategy combining RIG-I-driven immunization with CTLA-4 blockade to prevent and treat experimental melanoma. FUND: German Research Foundation (SFB 1335, SFB 1371), EMBO, Else Kröner-Fresenius-Foundation, German Cancer Aid, European Hematology Association, DKMS Foundation for Giving Life, Dres. Carl Maximilian and Carl Manfred Bayer-Foundation. Elsevier 2019-03-06 /pmc/articles/PMC6444128/ /pubmed/30852164 http://dx.doi.org/10.1016/j.ebiom.2019.02.056 Text en © 2019 The Authors. Published by Elsevier B.V. http://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 Research paper
Heidegger, Simon
Kreppel, Diana
Bscheider, Michael
Stritzke, Florian
Nedelko, Tatiana
Wintges, Alexander
Bek, Sarah
Fischer, Julius C.
Graalmann, Theresa
Kalinke, Ulrich
Bassermann, Florian
Haas, Tobias
Poeck, Hendrik
RIG-I activating immunostimulatory RNA boosts the efficacy of anticancer vaccines and synergizes with immune checkpoint blockade
title RIG-I activating immunostimulatory RNA boosts the efficacy of anticancer vaccines and synergizes with immune checkpoint blockade
title_full RIG-I activating immunostimulatory RNA boosts the efficacy of anticancer vaccines and synergizes with immune checkpoint blockade
title_fullStr RIG-I activating immunostimulatory RNA boosts the efficacy of anticancer vaccines and synergizes with immune checkpoint blockade
title_full_unstemmed RIG-I activating immunostimulatory RNA boosts the efficacy of anticancer vaccines and synergizes with immune checkpoint blockade
title_short RIG-I activating immunostimulatory RNA boosts the efficacy of anticancer vaccines and synergizes with immune checkpoint blockade
title_sort rig-i activating immunostimulatory rna boosts the efficacy of anticancer vaccines and synergizes with immune checkpoint blockade
topic Research paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444128/
https://www.ncbi.nlm.nih.gov/pubmed/30852164
http://dx.doi.org/10.1016/j.ebiom.2019.02.056
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