Cargando…

Intra-Tumoral Activation of Endosomal TLR Pathways Reveals a Distinct Role for TLR3 Agonist Dependent Type-1 Interferons in Shaping the Tumor Immune Microenvironment

Toll-like receptor (TLR) agonists have received considerable attention as therapeutic targets for cancer immunotherapy owing to their ability to convert immunosuppressive tumor microenvironments towards a more T-cell inflamed phenotype. However, TLRs differ in their cell expression profiles and intr...

Descripción completa

Detalles Bibliográficos
Autores principales: Thomas, Graham, Micci, Luca, Yang, Wenjing, Katakowski, Joseph, Oderup, Cecilia, Sundar, Purnima, Wang, Xiao, Geles, Kenneth G., Potluri, Shobha, Salek-Ardakani, Shahram
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351420/
https://www.ncbi.nlm.nih.gov/pubmed/34381732
http://dx.doi.org/10.3389/fonc.2021.711673
_version_ 1783735971058024448
author Thomas, Graham
Micci, Luca
Yang, Wenjing
Katakowski, Joseph
Oderup, Cecilia
Sundar, Purnima
Wang, Xiao
Geles, Kenneth G.
Potluri, Shobha
Salek-Ardakani, Shahram
author_facet Thomas, Graham
Micci, Luca
Yang, Wenjing
Katakowski, Joseph
Oderup, Cecilia
Sundar, Purnima
Wang, Xiao
Geles, Kenneth G.
Potluri, Shobha
Salek-Ardakani, Shahram
author_sort Thomas, Graham
collection PubMed
description Toll-like receptor (TLR) agonists have received considerable attention as therapeutic targets for cancer immunotherapy owing to their ability to convert immunosuppressive tumor microenvironments towards a more T-cell inflamed phenotype. However, TLRs differ in their cell expression profiles and intracellular signaling pathways, raising the possibility that distinct TLRs differentially influence the tumor immune microenvironment. Using single-cell RNA-sequencing, we address this by comparing the tumor immune composition of B16F10 melanoma following treatment with agonists of TLR3, TLR7, and TLR9. Marked differences are observed between treatments, including decreased tumor-associated macrophages upon TLR7 agonist treatment. A biased type-1 interferon signature is elicited upon TLR3 agonist treatment as opposed to a type-2 interferon signature with TLR9 agonists. TLR3 stimulation was associated with increased macrophage antigen presentation gene expression and decreased expression of PD-L1 and the inhibitory receptors Pirb and Pilra on infiltrating monocytes. Furthermore, in contrast to TLR7 and TLR9 agonists, TLR3 stimulation ablated FoxP3 positive CD4 T cells and elicited a distinct CD8 T cell activation phenotype highlighting the potential for distinct synergies between TLR agonists and combination therapy agents.
format Online
Article
Text
id pubmed-8351420
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-83514202021-08-10 Intra-Tumoral Activation of Endosomal TLR Pathways Reveals a Distinct Role for TLR3 Agonist Dependent Type-1 Interferons in Shaping the Tumor Immune Microenvironment Thomas, Graham Micci, Luca Yang, Wenjing Katakowski, Joseph Oderup, Cecilia Sundar, Purnima Wang, Xiao Geles, Kenneth G. Potluri, Shobha Salek-Ardakani, Shahram Front Oncol Oncology Toll-like receptor (TLR) agonists have received considerable attention as therapeutic targets for cancer immunotherapy owing to their ability to convert immunosuppressive tumor microenvironments towards a more T-cell inflamed phenotype. However, TLRs differ in their cell expression profiles and intracellular signaling pathways, raising the possibility that distinct TLRs differentially influence the tumor immune microenvironment. Using single-cell RNA-sequencing, we address this by comparing the tumor immune composition of B16F10 melanoma following treatment with agonists of TLR3, TLR7, and TLR9. Marked differences are observed between treatments, including decreased tumor-associated macrophages upon TLR7 agonist treatment. A biased type-1 interferon signature is elicited upon TLR3 agonist treatment as opposed to a type-2 interferon signature with TLR9 agonists. TLR3 stimulation was associated with increased macrophage antigen presentation gene expression and decreased expression of PD-L1 and the inhibitory receptors Pirb and Pilra on infiltrating monocytes. Furthermore, in contrast to TLR7 and TLR9 agonists, TLR3 stimulation ablated FoxP3 positive CD4 T cells and elicited a distinct CD8 T cell activation phenotype highlighting the potential for distinct synergies between TLR agonists and combination therapy agents. Frontiers Media S.A. 2021-07-26 /pmc/articles/PMC8351420/ /pubmed/34381732 http://dx.doi.org/10.3389/fonc.2021.711673 Text en Copyright © 2021 Thomas, Micci, Yang, Katakowski, Oderup, Sundar, Wang, Geles, Potluri and Salek-Ardakani https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Thomas, Graham
Micci, Luca
Yang, Wenjing
Katakowski, Joseph
Oderup, Cecilia
Sundar, Purnima
Wang, Xiao
Geles, Kenneth G.
Potluri, Shobha
Salek-Ardakani, Shahram
Intra-Tumoral Activation of Endosomal TLR Pathways Reveals a Distinct Role for TLR3 Agonist Dependent Type-1 Interferons in Shaping the Tumor Immune Microenvironment
title Intra-Tumoral Activation of Endosomal TLR Pathways Reveals a Distinct Role for TLR3 Agonist Dependent Type-1 Interferons in Shaping the Tumor Immune Microenvironment
title_full Intra-Tumoral Activation of Endosomal TLR Pathways Reveals a Distinct Role for TLR3 Agonist Dependent Type-1 Interferons in Shaping the Tumor Immune Microenvironment
title_fullStr Intra-Tumoral Activation of Endosomal TLR Pathways Reveals a Distinct Role for TLR3 Agonist Dependent Type-1 Interferons in Shaping the Tumor Immune Microenvironment
title_full_unstemmed Intra-Tumoral Activation of Endosomal TLR Pathways Reveals a Distinct Role for TLR3 Agonist Dependent Type-1 Interferons in Shaping the Tumor Immune Microenvironment
title_short Intra-Tumoral Activation of Endosomal TLR Pathways Reveals a Distinct Role for TLR3 Agonist Dependent Type-1 Interferons in Shaping the Tumor Immune Microenvironment
title_sort intra-tumoral activation of endosomal tlr pathways reveals a distinct role for tlr3 agonist dependent type-1 interferons in shaping the tumor immune microenvironment
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351420/
https://www.ncbi.nlm.nih.gov/pubmed/34381732
http://dx.doi.org/10.3389/fonc.2021.711673
work_keys_str_mv AT thomasgraham intratumoralactivationofendosomaltlrpathwaysrevealsadistinctrolefortlr3agonistdependenttype1interferonsinshapingthetumorimmunemicroenvironment
AT micciluca intratumoralactivationofendosomaltlrpathwaysrevealsadistinctrolefortlr3agonistdependenttype1interferonsinshapingthetumorimmunemicroenvironment
AT yangwenjing intratumoralactivationofendosomaltlrpathwaysrevealsadistinctrolefortlr3agonistdependenttype1interferonsinshapingthetumorimmunemicroenvironment
AT katakowskijoseph intratumoralactivationofendosomaltlrpathwaysrevealsadistinctrolefortlr3agonistdependenttype1interferonsinshapingthetumorimmunemicroenvironment
AT oderupcecilia intratumoralactivationofendosomaltlrpathwaysrevealsadistinctrolefortlr3agonistdependenttype1interferonsinshapingthetumorimmunemicroenvironment
AT sundarpurnima intratumoralactivationofendosomaltlrpathwaysrevealsadistinctrolefortlr3agonistdependenttype1interferonsinshapingthetumorimmunemicroenvironment
AT wangxiao intratumoralactivationofendosomaltlrpathwaysrevealsadistinctrolefortlr3agonistdependenttype1interferonsinshapingthetumorimmunemicroenvironment
AT geleskennethg intratumoralactivationofendosomaltlrpathwaysrevealsadistinctrolefortlr3agonistdependenttype1interferonsinshapingthetumorimmunemicroenvironment
AT potlurishobha intratumoralactivationofendosomaltlrpathwaysrevealsadistinctrolefortlr3agonistdependenttype1interferonsinshapingthetumorimmunemicroenvironment
AT salekardakanishahram intratumoralactivationofendosomaltlrpathwaysrevealsadistinctrolefortlr3agonistdependenttype1interferonsinshapingthetumorimmunemicroenvironment