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Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma

Lung adenocarcinoma (LUAD)-derived Wnts increase cancer cell proliferative/stemness potential, but whether they impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. In TCGA, Wnt1 correlates strongly with tolerogenic gen...

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Autores principales: Kerdidani, Dimitra, Chouvardas, Panagiotis, Arjo, Ares Rocanin, Giopanou, Ioanna, Ntaliarda, Giannoula, Guo, Yu Amanda, Tsikitis, Mary, Kazamias, Georgios, Potaris, Konstantinos, Stathopoulos, Georgios T., Zakynthinos, Spyros, Kalomenidis, Ioannis, Soumelis, Vassili, Kollias, George, Tsoumakidou, Maria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441097/
https://www.ncbi.nlm.nih.gov/pubmed/30926812
http://dx.doi.org/10.1038/s41467-019-09370-z
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author Kerdidani, Dimitra
Chouvardas, Panagiotis
Arjo, Ares Rocanin
Giopanou, Ioanna
Ntaliarda, Giannoula
Guo, Yu Amanda
Tsikitis, Mary
Kazamias, Georgios
Potaris, Konstantinos
Stathopoulos, Georgios T.
Zakynthinos, Spyros
Kalomenidis, Ioannis
Soumelis, Vassili
Kollias, George
Tsoumakidou, Maria
author_facet Kerdidani, Dimitra
Chouvardas, Panagiotis
Arjo, Ares Rocanin
Giopanou, Ioanna
Ntaliarda, Giannoula
Guo, Yu Amanda
Tsikitis, Mary
Kazamias, Georgios
Potaris, Konstantinos
Stathopoulos, Georgios T.
Zakynthinos, Spyros
Kalomenidis, Ioannis
Soumelis, Vassili
Kollias, George
Tsoumakidou, Maria
author_sort Kerdidani, Dimitra
collection PubMed
description Lung adenocarcinoma (LUAD)-derived Wnts increase cancer cell proliferative/stemness potential, but whether they impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. In TCGA, Wnt1 correlates strongly with tolerogenic genes. In another LUAD cohort, Wnt1 inversely associates with T cell abundance. Altering Wnt1 expression profoundly affects growth of murine lung adenocarcinomas and this is dependent on conventional dendritic cells (cDCs) and T cells. Mechanistically, Wnt1 leads to transcriptional silencing of CC/CXC chemokines in cDCs, T cell exclusion and cross-tolerance. Wnt-target genes are up-regulated in human intratumoral cDCs and decrease upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-nanoparticles given as single therapy or part of combinatorial immunotherapies act at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 induces immunologically cold tumors through cDCs and highlight its immunotherapeutic targeting.
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spelling pubmed-64410972019-04-01 Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma Kerdidani, Dimitra Chouvardas, Panagiotis Arjo, Ares Rocanin Giopanou, Ioanna Ntaliarda, Giannoula Guo, Yu Amanda Tsikitis, Mary Kazamias, Georgios Potaris, Konstantinos Stathopoulos, Georgios T. Zakynthinos, Spyros Kalomenidis, Ioannis Soumelis, Vassili Kollias, George Tsoumakidou, Maria Nat Commun Article Lung adenocarcinoma (LUAD)-derived Wnts increase cancer cell proliferative/stemness potential, but whether they impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. In TCGA, Wnt1 correlates strongly with tolerogenic genes. In another LUAD cohort, Wnt1 inversely associates with T cell abundance. Altering Wnt1 expression profoundly affects growth of murine lung adenocarcinomas and this is dependent on conventional dendritic cells (cDCs) and T cells. Mechanistically, Wnt1 leads to transcriptional silencing of CC/CXC chemokines in cDCs, T cell exclusion and cross-tolerance. Wnt-target genes are up-regulated in human intratumoral cDCs and decrease upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-nanoparticles given as single therapy or part of combinatorial immunotherapies act at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 induces immunologically cold tumors through cDCs and highlight its immunotherapeutic targeting. Nature Publishing Group UK 2019-03-29 /pmc/articles/PMC6441097/ /pubmed/30926812 http://dx.doi.org/10.1038/s41467-019-09370-z Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Kerdidani, Dimitra
Chouvardas, Panagiotis
Arjo, Ares Rocanin
Giopanou, Ioanna
Ntaliarda, Giannoula
Guo, Yu Amanda
Tsikitis, Mary
Kazamias, Georgios
Potaris, Konstantinos
Stathopoulos, Georgios T.
Zakynthinos, Spyros
Kalomenidis, Ioannis
Soumelis, Vassili
Kollias, George
Tsoumakidou, Maria
Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma
title Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma
title_full Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma
title_fullStr Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma
title_full_unstemmed Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma
title_short Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma
title_sort wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441097/
https://www.ncbi.nlm.nih.gov/pubmed/30926812
http://dx.doi.org/10.1038/s41467-019-09370-z
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