TY - JOUR
T1 - Immunomodulation of T Helper Cells by Tumor Microenvironment in Oral Cancer Is Associated With CCR8 Expression and Rapid Membrane Vitamin D Signaling Pathway
AU - Fraga, Marco
AU - Yáñez, Milly
AU - Sherman, Macarena
AU - Llerena, Faryd
AU - Hernandez, Mauricio
AU - Nourdin, Guillermo
AU - Álvarez, Francisco
AU - Urrizola, Joaquín
AU - Rivera, César
AU - Lamperti, Liliana
AU - Nova, Lorena
AU - Castro, Silvia
AU - Zambrano, Omar
AU - Cifuentes, Alejandro
AU - Campos, León
AU - Moya, Sergio
AU - Pastor, Juan
AU - Nuñez, Marcelo
AU - Gatica, Jorge
AU - Figueroa, Jorge
AU - Zúñiga, Felipe
AU - Salomón, Carlos
AU - Cerda, Gustavo
AU - Puentes, Ricardo
AU - Labarca, Gonzalo
AU - Vidal, Mabel
AU - McGregor, Reuben
AU - Nova-Lamperti, Estefania
N1 - Publisher Copyright:
© 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.
PY - 2021/5/7
Y1 - 2021/5/7
N2 - 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.
AB - 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.
KW - CCR8
KW - Th-like Tregs
KW - cancer immunology
KW - immunomodulation
KW - oral cancer
UR - http://www.scopus.com/inward/record.url?scp=85106151714&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.643298
DO - 10.3389/fimmu.2021.643298
M3 - Article
C2 - 34025655
AN - SCOPUS:85106151714
SN - 1664-3224
VL - 12
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 643298
ER -
