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IAP inhibitors enhance co-stimulation to promote tumor immunity

The inhibitor of apoptosis proteins (IAPs) have recently been shown to modulate nuclear factor κB (NF-κB) signaling downstream of tumor necrosis factor (TNF) family receptors, positioning them as essential survival factors in several cancer cell lines, as indicated by the cytotoxic activity of sever...

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Autores principales: Dougan, Michael, Dougan, Stephanie, Slisz, Joanna, Firestone, Brant, Vanneman, Matthew, Draganov, Dobrin, Goyal, Girija, Li, Weibo, Neuberg, Donna, Blumberg, Richard, Hacohen, Nir, Porter, Dale, Zawel, Leigh, Dranoff, Glenn
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947073/
https://www.ncbi.nlm.nih.gov/pubmed/20837698
http://dx.doi.org/10.1084/jem.20101123
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author Dougan, Michael
Dougan, Stephanie
Slisz, Joanna
Firestone, Brant
Vanneman, Matthew
Draganov, Dobrin
Goyal, Girija
Li, Weibo
Neuberg, Donna
Blumberg, Richard
Hacohen, Nir
Porter, Dale
Zawel, Leigh
Dranoff, Glenn
author_facet Dougan, Michael
Dougan, Stephanie
Slisz, Joanna
Firestone, Brant
Vanneman, Matthew
Draganov, Dobrin
Goyal, Girija
Li, Weibo
Neuberg, Donna
Blumberg, Richard
Hacohen, Nir
Porter, Dale
Zawel, Leigh
Dranoff, Glenn
author_sort Dougan, Michael
collection PubMed
description The inhibitor of apoptosis proteins (IAPs) have recently been shown to modulate nuclear factor κB (NF-κB) signaling downstream of tumor necrosis factor (TNF) family receptors, positioning them as essential survival factors in several cancer cell lines, as indicated by the cytotoxic activity of several novel small molecule IAP antagonists. In addition to roles in cancer, increasing evidence suggests that IAPs have an important function in immunity; however, the impact of IAP antagonists on antitumor immune responses is unknown. In this study, we examine the consequences of IAP antagonism on T cell function in vitro and in the context of a tumor vaccine in vivo. We find that IAP antagonists can augment human and mouse T cell responses to physiologically relevant stimuli. The activity of IAP antagonists depends on the activation of NF-κB2 signaling, a mechanism paralleling that responsible for the cytotoxic activity in cancer cells. We further show that IAP antagonists can augment both prophylactic and therapeutic antitumor vaccines in vivo. These findings indicate an important role for the IAPs in regulating T cell–dependent responses and suggest that targeting IAPs using small molecule antagonists may be a strategy for developing novel immunomodulating therapies against cancer.
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spelling pubmed-29470732011-03-27 IAP inhibitors enhance co-stimulation to promote tumor immunity Dougan, Michael Dougan, Stephanie Slisz, Joanna Firestone, Brant Vanneman, Matthew Draganov, Dobrin Goyal, Girija Li, Weibo Neuberg, Donna Blumberg, Richard Hacohen, Nir Porter, Dale Zawel, Leigh Dranoff, Glenn J Exp Med Article The inhibitor of apoptosis proteins (IAPs) have recently been shown to modulate nuclear factor κB (NF-κB) signaling downstream of tumor necrosis factor (TNF) family receptors, positioning them as essential survival factors in several cancer cell lines, as indicated by the cytotoxic activity of several novel small molecule IAP antagonists. In addition to roles in cancer, increasing evidence suggests that IAPs have an important function in immunity; however, the impact of IAP antagonists on antitumor immune responses is unknown. In this study, we examine the consequences of IAP antagonism on T cell function in vitro and in the context of a tumor vaccine in vivo. We find that IAP antagonists can augment human and mouse T cell responses to physiologically relevant stimuli. The activity of IAP antagonists depends on the activation of NF-κB2 signaling, a mechanism paralleling that responsible for the cytotoxic activity in cancer cells. We further show that IAP antagonists can augment both prophylactic and therapeutic antitumor vaccines in vivo. These findings indicate an important role for the IAPs in regulating T cell–dependent responses and suggest that targeting IAPs using small molecule antagonists may be a strategy for developing novel immunomodulating therapies against cancer. The Rockefeller University Press 2010-09-27 /pmc/articles/PMC2947073/ /pubmed/20837698 http://dx.doi.org/10.1084/jem.20101123 Text en © 2010 Dougan et al. 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 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Dougan, Michael
Dougan, Stephanie
Slisz, Joanna
Firestone, Brant
Vanneman, Matthew
Draganov, Dobrin
Goyal, Girija
Li, Weibo
Neuberg, Donna
Blumberg, Richard
Hacohen, Nir
Porter, Dale
Zawel, Leigh
Dranoff, Glenn
IAP inhibitors enhance co-stimulation to promote tumor immunity
title IAP inhibitors enhance co-stimulation to promote tumor immunity
title_full IAP inhibitors enhance co-stimulation to promote tumor immunity
title_fullStr IAP inhibitors enhance co-stimulation to promote tumor immunity
title_full_unstemmed IAP inhibitors enhance co-stimulation to promote tumor immunity
title_short IAP inhibitors enhance co-stimulation to promote tumor immunity
title_sort iap inhibitors enhance co-stimulation to promote tumor immunity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947073/
https://www.ncbi.nlm.nih.gov/pubmed/20837698
http://dx.doi.org/10.1084/jem.20101123
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