OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4+ T cells

OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4+ T cells

Adoptive therapy with chimeric antigen receptor (CAR) redirected T cells recently showed remarkable anti-tumor efficacy in early phase clinical trials; self-repression of the immune response by T-cell secreted cytokines, however, is still an issue raising interest to abrogate the secretion of repres...

Full description

Bibliographic Details
Main Authors: Hombach, Andreas A., Heiders, Johannes, Foppe, Marcel, Chmielewski, Markus, Abken, Hinrich
Format: Online
Language:English
Published: Landes Bioscience 2012
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382912/
id pubmed-3382912
recordtype oai_dc
spelling pubmed-33829122012-07-01 OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4+ T cells Hombach, Andreas A. Heiders, Johannes Foppe, Marcel Chmielewski, Markus Abken, Hinrich Research Paper Adoptive therapy with chimeric antigen receptor (CAR) redirected T cells recently showed remarkable anti-tumor efficacy in early phase clinical trials; self-repression of the immune response by T-cell secreted cytokines, however, is still an issue raising interest to abrogate the secretion of repressive cytokines while preserving the panel of CAR induced pro-inflammatory cytokines. We here revealed that T-cell activation by a CD28-ζ signaling CAR induced IL-10 secretion, which compromises T cell based immunity, along with the release of pro-inflammatory IFN-γ and IL-2. T cells stimulated by a ζ CAR without costimulation did not secrete IL-2 or IL-10; the latter, however, could be induced by supplementation with IL-2. Abrogation of CD28-ζ CAR induced IL-2 release by CD28 mutation did not reduce IL-10 secretion indicating that IL-10 can be induced by both a CD28 and an IL-2 mediated pathway. In contrast to the CD28-ζ CAR, a CAR with OX40 (CD134) costimulation did not induce IL-10. OX40 cosignaling by a 3rd generation CD28-ζ-OX40 CAR repressed CD28 induced IL-10 secretion but did not affect the secretion of pro-inflammatory cytokines, T-cell amplification or T-cell mediated cytolysis. IL-2 induced IL-10 was also repressed by OX40 co-signaling. OX40 moreover repressed IL-10 secretion by regulatory T cells which are strong IL-10 producers upon activation. Taken together OX40 cosignaling in CAR redirected T cell activation effectively represses IL-10 secretion which contributes to counteract self-repression and provides a rationale to explore OX40 co-signaling CARs in order to prolong a redirected T cell response. Landes Bioscience 2012-07-01 /pmc/articles/PMC3382912/ /pubmed/22754764 Text en Copyright © 2012 Landes Bioscience http://creativecommons.org/licenses/by-nc/3.0/ This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Hombach, Andreas A.
Heiders, Johannes
Foppe, Marcel
Chmielewski, Markus
Abken, Hinrich
spellingShingle Hombach, Andreas A.
Heiders, Johannes
Foppe, Marcel
Chmielewski, Markus
Abken, Hinrich
OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4+ T cells
author_facet Hombach, Andreas A.
Heiders, Johannes
Foppe, Marcel
Chmielewski, Markus
Abken, Hinrich
author_sort Hombach, Andreas A.
title OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4+ T cells
title_short OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4+ T cells
title_full OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4+ T cells
title_fullStr OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4+ T cells
title_full_unstemmed OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4+ T cells
title_sort ox40 costimulation by a chimeric antigen receptor abrogates cd28 and il-2 induced il-10 secretion by redirected cd4+ t cells
description Adoptive therapy with chimeric antigen receptor (CAR) redirected T cells recently showed remarkable anti-tumor efficacy in early phase clinical trials; self-repression of the immune response by T-cell secreted cytokines, however, is still an issue raising interest to abrogate the secretion of repressive cytokines while preserving the panel of CAR induced pro-inflammatory cytokines. We here revealed that T-cell activation by a CD28-ζ signaling CAR induced IL-10 secretion, which compromises T cell based immunity, along with the release of pro-inflammatory IFN-γ and IL-2. T cells stimulated by a ζ CAR without costimulation did not secrete IL-2 or IL-10; the latter, however, could be induced by supplementation with IL-2. Abrogation of CD28-ζ CAR induced IL-2 release by CD28 mutation did not reduce IL-10 secretion indicating that IL-10 can be induced by both a CD28 and an IL-2 mediated pathway. In contrast to the CD28-ζ CAR, a CAR with OX40 (CD134) costimulation did not induce IL-10. OX40 cosignaling by a 3rd generation CD28-ζ-OX40 CAR repressed CD28 induced IL-10 secretion but did not affect the secretion of pro-inflammatory cytokines, T-cell amplification or T-cell mediated cytolysis. IL-2 induced IL-10 was also repressed by OX40 co-signaling. OX40 moreover repressed IL-10 secretion by regulatory T cells which are strong IL-10 producers upon activation. Taken together OX40 cosignaling in CAR redirected T cell activation effectively represses IL-10 secretion which contributes to counteract self-repression and provides a rationale to explore OX40 co-signaling CARs in order to prolong a redirected T cell response.
publisher Landes Bioscience
publishDate 2012
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382912/
_version_ 1611539074372337664

Similar Items