Immunomodulation of T Helper Cells by Tumor Microenvironment in Oral Cancer Is Associated With CCR8 Expression and Rapid Membrane Vitamin D Signaling Pathway

The immune system plays a key role in the protective response against oral cancer; however, the tumor microenvironment (TME) impairs this anti-cancer response by modulating T helper (Th) responses and promoting an anti-inflammatory environment. Regulatory T cells (Tregs) and Th2 effector cells (Teff...

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Autores principales: Fraga, Marco, Yáñez, Milly, Sherman, Macarena, Llerena, Faryd, Hernandez, Mauricio, Nourdin, Guillermo, Álvarez, Francisco, Urrizola, Joaquín, Rivera, César, Lamperti, Liliana, Nova, Lorena, Castro, Silvia, Zambrano, Omar, Cifuentes, Alejandro, Campos, León, Moya, Sergio, Pastor, Juan, Nuñez, Marcelo, Gatica, Jorge, Figueroa, Jorge, Zúñiga, Felipe, Salomón, Carlos, Cerda, Gustavo, Puentes, Ricardo, Labarca, Gonzalo, Vidal, Mabel, McGregor, Reuben, Nova-Lamperti, Estefania
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137990/
https://www.ncbi.nlm.nih.gov/pubmed/34025655
http://dx.doi.org/10.3389/fimmu.2021.643298
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author Fraga, Marco
Yáñez, Milly
Sherman, Macarena
Llerena, Faryd
Hernandez, Mauricio
Nourdin, Guillermo
Álvarez, Francisco
Urrizola, Joaquín
Rivera, César
Lamperti, Liliana
Nova, Lorena
Castro, Silvia
Zambrano, Omar
Cifuentes, Alejandro
Campos, León
Moya, Sergio
Pastor, Juan
Nuñez, Marcelo
Gatica, Jorge
Figueroa, Jorge
Zúñiga, Felipe
Salomón, Carlos
Cerda, Gustavo
Puentes, Ricardo
Labarca, Gonzalo
Vidal, Mabel
McGregor, Reuben
Nova-Lamperti, Estefania
author_facet Fraga, Marco
Yáñez, Milly
Sherman, Macarena
Llerena, Faryd
Hernandez, Mauricio
Nourdin, Guillermo
Álvarez, Francisco
Urrizola, Joaquín
Rivera, César
Lamperti, Liliana
Nova, Lorena
Castro, Silvia
Zambrano, Omar
Cifuentes, Alejandro
Campos, León
Moya, Sergio
Pastor, Juan
Nuñez, Marcelo
Gatica, Jorge
Figueroa, Jorge
Zúñiga, Felipe
Salomón, Carlos
Cerda, Gustavo
Puentes, Ricardo
Labarca, Gonzalo
Vidal, Mabel
McGregor, Reuben
Nova-Lamperti, Estefania
author_sort Fraga, Marco
collection PubMed
description The immune system plays a key role in the protective response against oral cancer; however, the tumor microenvironment (TME) impairs this anti-cancer response by modulating T helper (Th) responses and promoting an anti-inflammatory environment. Regulatory T cells (Tregs) and Th2 effector cells (Teff) are associated with poor prognosis in oral squamous cell carcinoma (OSCC). However, the main immunomodulatory mechanisms associated with the enrichment of these subsets in OSCC remain unknown. We characterized Th-like lineages in Tregs and Teff and evaluated immunomodulatory changes induced by the TME in OSCC. Our phenotypic data revealed a higher distribution of tumour-infiltrating CCR8(+) and Th2-like Treg in OSCC compared with non-malignant samples, whereas the percentages of Th1 cells were reduced in cancer. We then analyzed the direct effect of the TME by exposing T cell subsets to cancer secretomes and observed the OSCC secretome induced CCR8 expression and reduced cytokine production from both subsets. Transcriptomic analysis showed that the co-culture with OSCC secretome induced several gene changes associated with the vitamin D (VitD) signaling pathway in T cells. In addition, proteomic analysis identified the presence of several proteins associated with prostaglandin E2 (PGE2) production by rapid membrane VitD signaling and a reduced presence of the VitD binding protein. Thus, we analyzed the effect of VitD and PGE2 and observed that VitD promotes a regulatory Th2-like response with CCR8 expression whilst PGE2 also modulated CCR8 but inhibited cytokine production in combination with VitD. Finally, we evaluated the presence of CCR8 ligand in OSCC and observed increased chemokine CCL18, which was also able to upregulate CCR8 in activated Th cells. Overall, our data showed the immunomodulatory changes induced by the TME involving CCR8 expression and regulatory Th2 phenotypes, which are associated with PGE2 mediated VitD signaling pathway and CCL18 expression in OSCC.
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spelling pubmed-81379902021-05-22 Immunomodulation of T Helper Cells by Tumor Microenvironment in Oral Cancer Is Associated With CCR8 Expression and Rapid Membrane Vitamin D Signaling Pathway Fraga, Marco Yáñez, Milly Sherman, Macarena Llerena, Faryd Hernandez, Mauricio Nourdin, Guillermo Álvarez, Francisco Urrizola, Joaquín Rivera, César Lamperti, Liliana Nova, Lorena Castro, Silvia Zambrano, Omar Cifuentes, Alejandro Campos, León Moya, Sergio Pastor, Juan Nuñez, Marcelo Gatica, Jorge Figueroa, Jorge Zúñiga, Felipe Salomón, Carlos Cerda, Gustavo Puentes, Ricardo Labarca, Gonzalo Vidal, Mabel McGregor, Reuben Nova-Lamperti, Estefania Front Immunol Immunology The immune system plays a key role in the protective response against oral cancer; however, the tumor microenvironment (TME) impairs this anti-cancer response by modulating T helper (Th) responses and promoting an anti-inflammatory environment. Regulatory T cells (Tregs) and Th2 effector cells (Teff) are associated with poor prognosis in oral squamous cell carcinoma (OSCC). However, the main immunomodulatory mechanisms associated with the enrichment of these subsets in OSCC remain unknown. We characterized Th-like lineages in Tregs and Teff and evaluated immunomodulatory changes induced by the TME in OSCC. Our phenotypic data revealed a higher distribution of tumour-infiltrating CCR8(+) and Th2-like Treg in OSCC compared with non-malignant samples, whereas the percentages of Th1 cells were reduced in cancer. We then analyzed the direct effect of the TME by exposing T cell subsets to cancer secretomes and observed the OSCC secretome induced CCR8 expression and reduced cytokine production from both subsets. Transcriptomic analysis showed that the co-culture with OSCC secretome induced several gene changes associated with the vitamin D (VitD) signaling pathway in T cells. In addition, proteomic analysis identified the presence of several proteins associated with prostaglandin E2 (PGE2) production by rapid membrane VitD signaling and a reduced presence of the VitD binding protein. Thus, we analyzed the effect of VitD and PGE2 and observed that VitD promotes a regulatory Th2-like response with CCR8 expression whilst PGE2 also modulated CCR8 but inhibited cytokine production in combination with VitD. Finally, we evaluated the presence of CCR8 ligand in OSCC and observed increased chemokine CCL18, which was also able to upregulate CCR8 in activated Th cells. Overall, our data showed the immunomodulatory changes induced by the TME involving CCR8 expression and regulatory Th2 phenotypes, which are associated with PGE2 mediated VitD signaling pathway and CCL18 expression in OSCC. Frontiers Media S.A. 2021-05-07 /pmc/articles/PMC8137990/ /pubmed/34025655 http://dx.doi.org/10.3389/fimmu.2021.643298 Text en Copyright © 2021 Fraga, Yáñez, Sherman, Llerena, Hernandez, Nourdin, Álvarez, Urrizola, Rivera, Lamperti, Nova, Castro, Zambrano, Cifuentes, Campos, Moya, Pastor, Nuñez, Gatica, Figueroa, Zúñiga, Salomón, Cerda, Puentes, Labarca, Vidal, McGregor and Nova-Lamperti 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 Immunology
Fraga, Marco
Yáñez, Milly
Sherman, Macarena
Llerena, Faryd
Hernandez, Mauricio
Nourdin, Guillermo
Álvarez, Francisco
Urrizola, Joaquín
Rivera, César
Lamperti, Liliana
Nova, Lorena
Castro, Silvia
Zambrano, Omar
Cifuentes, Alejandro
Campos, León
Moya, Sergio
Pastor, Juan
Nuñez, Marcelo
Gatica, Jorge
Figueroa, Jorge
Zúñiga, Felipe
Salomón, Carlos
Cerda, Gustavo
Puentes, Ricardo
Labarca, Gonzalo
Vidal, Mabel
McGregor, Reuben
Nova-Lamperti, Estefania
Immunomodulation of T Helper Cells by Tumor Microenvironment in Oral Cancer Is Associated With CCR8 Expression and Rapid Membrane Vitamin D Signaling Pathway
title Immunomodulation of T Helper Cells by Tumor Microenvironment in Oral Cancer Is Associated With CCR8 Expression and Rapid Membrane Vitamin D Signaling Pathway
title_full Immunomodulation of T Helper Cells by Tumor Microenvironment in Oral Cancer Is Associated With CCR8 Expression and Rapid Membrane Vitamin D Signaling Pathway
title_fullStr Immunomodulation of T Helper Cells by Tumor Microenvironment in Oral Cancer Is Associated With CCR8 Expression and Rapid Membrane Vitamin D Signaling Pathway
title_full_unstemmed Immunomodulation of T Helper Cells by Tumor Microenvironment in Oral Cancer Is Associated With CCR8 Expression and Rapid Membrane Vitamin D Signaling Pathway
title_short Immunomodulation of T Helper Cells by Tumor Microenvironment in Oral Cancer Is Associated With CCR8 Expression and Rapid Membrane Vitamin D Signaling Pathway
title_sort immunomodulation of t helper cells by tumor microenvironment in oral cancer is associated with ccr8 expression and rapid membrane vitamin d signaling pathway
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137990/
https://www.ncbi.nlm.nih.gov/pubmed/34025655
http://dx.doi.org/10.3389/fimmu.2021.643298
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