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Concurrent OX40 and CD30 Ligand Blockade Abrogates the CD4-Driven Autoimmunity Associated with CTLA4 and PD1 Blockade while Preserving Excellent Anti-CD8 Tumor Immunity

Although strategies that block FOXP3-dependent regulatory T cell function (CTLA4 blockade) and the inhibitory receptor PD1 have shown great promise in promoting antitumor immune responses in humans, their widespread implementation for cancer immunotherapy has been hampered by significant off-target...

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Autores principales: Nawaf, Maher G., Ulvmar, Maria H., Withers, David R., McConnell, Fiona M., Gaspal, Fabrina M., Webb, Gwilym J., Jones, Nick D., Yagita, Hideo, Allison, James P., Lane, Peter J. L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AAI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5523579/
https://www.ncbi.nlm.nih.gov/pubmed/28646041
http://dx.doi.org/10.4049/jimmunol.1700088
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author Nawaf, Maher G.
Ulvmar, Maria H.
Withers, David R.
McConnell, Fiona M.
Gaspal, Fabrina M.
Webb, Gwilym J.
Jones, Nick D.
Yagita, Hideo
Allison, James P.
Lane, Peter J. L.
author_facet Nawaf, Maher G.
Ulvmar, Maria H.
Withers, David R.
McConnell, Fiona M.
Gaspal, Fabrina M.
Webb, Gwilym J.
Jones, Nick D.
Yagita, Hideo
Allison, James P.
Lane, Peter J. L.
author_sort Nawaf, Maher G.
collection PubMed
description Although strategies that block FOXP3-dependent regulatory T cell function (CTLA4 blockade) and the inhibitory receptor PD1 have shown great promise in promoting antitumor immune responses in humans, their widespread implementation for cancer immunotherapy has been hampered by significant off-target autoimmune side effects that can be lethal. Our work has shown that absence of OX40 and CD30 costimulatory signals prevents CD4 T cell–driven autoimmunity in Foxp3-deficient mice, suggesting a novel way to block these side effects. In this study, we show that excellent antitumor CD8 T cell responses can be achieved in Foxp3(KO) mice deficient in OX40 and CD30 signals, particularly in the presence of concurrent PD1 blockade. Furthermore, excellent antitumor immune responses can also be achieved using combinations of Abs that block CTLA4, PD1, OX40, and CD30 ligands, without CD4 T cell–driven autoimmunity. By dissociating autoimmune side effects from anticancer immune responses, this potentially shifts this antitumor approach to patients with far less advanced disease.
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spelling pubmed-55235792017-07-27 Concurrent OX40 and CD30 Ligand Blockade Abrogates the CD4-Driven Autoimmunity Associated with CTLA4 and PD1 Blockade while Preserving Excellent Anti-CD8 Tumor Immunity Nawaf, Maher G. Ulvmar, Maria H. Withers, David R. McConnell, Fiona M. Gaspal, Fabrina M. Webb, Gwilym J. Jones, Nick D. Yagita, Hideo Allison, James P. Lane, Peter J. L. J Immunol Immunotherapy and Vaccines Although strategies that block FOXP3-dependent regulatory T cell function (CTLA4 blockade) and the inhibitory receptor PD1 have shown great promise in promoting antitumor immune responses in humans, their widespread implementation for cancer immunotherapy has been hampered by significant off-target autoimmune side effects that can be lethal. Our work has shown that absence of OX40 and CD30 costimulatory signals prevents CD4 T cell–driven autoimmunity in Foxp3-deficient mice, suggesting a novel way to block these side effects. In this study, we show that excellent antitumor CD8 T cell responses can be achieved in Foxp3(KO) mice deficient in OX40 and CD30 signals, particularly in the presence of concurrent PD1 blockade. Furthermore, excellent antitumor immune responses can also be achieved using combinations of Abs that block CTLA4, PD1, OX40, and CD30 ligands, without CD4 T cell–driven autoimmunity. By dissociating autoimmune side effects from anticancer immune responses, this potentially shifts this antitumor approach to patients with far less advanced disease. AAI 2017-08-01 2017-06-23 /pmc/articles/PMC5523579/ /pubmed/28646041 http://dx.doi.org/10.4049/jimmunol.1700088 Text en Copyright © 2017 The Authors https://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the CC BY 4.0 Unported license.
spellingShingle Immunotherapy and Vaccines
Nawaf, Maher G.
Ulvmar, Maria H.
Withers, David R.
McConnell, Fiona M.
Gaspal, Fabrina M.
Webb, Gwilym J.
Jones, Nick D.
Yagita, Hideo
Allison, James P.
Lane, Peter J. L.
Concurrent OX40 and CD30 Ligand Blockade Abrogates the CD4-Driven Autoimmunity Associated with CTLA4 and PD1 Blockade while Preserving Excellent Anti-CD8 Tumor Immunity
title Concurrent OX40 and CD30 Ligand Blockade Abrogates the CD4-Driven Autoimmunity Associated with CTLA4 and PD1 Blockade while Preserving Excellent Anti-CD8 Tumor Immunity
title_full Concurrent OX40 and CD30 Ligand Blockade Abrogates the CD4-Driven Autoimmunity Associated with CTLA4 and PD1 Blockade while Preserving Excellent Anti-CD8 Tumor Immunity
title_fullStr Concurrent OX40 and CD30 Ligand Blockade Abrogates the CD4-Driven Autoimmunity Associated with CTLA4 and PD1 Blockade while Preserving Excellent Anti-CD8 Tumor Immunity
title_full_unstemmed Concurrent OX40 and CD30 Ligand Blockade Abrogates the CD4-Driven Autoimmunity Associated with CTLA4 and PD1 Blockade while Preserving Excellent Anti-CD8 Tumor Immunity
title_short Concurrent OX40 and CD30 Ligand Blockade Abrogates the CD4-Driven Autoimmunity Associated with CTLA4 and PD1 Blockade while Preserving Excellent Anti-CD8 Tumor Immunity
title_sort concurrent ox40 and cd30 ligand blockade abrogates the cd4-driven autoimmunity associated with ctla4 and pd1 blockade while preserving excellent anti-cd8 tumor immunity
topic Immunotherapy and Vaccines
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5523579/
https://www.ncbi.nlm.nih.gov/pubmed/28646041
http://dx.doi.org/10.4049/jimmunol.1700088
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