Enrichment of Human CCR6+ Regulatory T Cells with Superior Suppressive Activity in Oral Cancer

Abstract

Human oral squamous cell carcinoma (OSCC) constitutes an inflammatory microenvironment enriched with chemokines such as CCL20, which promote cancer cell invasion and tumor progression. We found that in OSCC there is a correlation between the expression of and mRNA. Therefore, we hypothesized that OSCC may favor the recruitment and retention of regulatory T (Treg) cells that express the CCL20 receptor, CCR6. Interestingly, most (∼60%) peripheral blood Treg cells express CCR6, and CCR6 Treg cells exhibit an activated effector/memory phenotype. In contrast, a significant portion (>30%) of CCR6 Treg cells were found to be CD45RA naive Treg cells. Compared to CCR6 naive or memory Treg cells, CCR6 Treg cells exhibit stronger suppressive activity and display higher FOXP3 expression along with lower methylation at the Treg-specific demethylated region of the gene. This predominance of CCR6 Treg cells was also found in the draining lymph nodes and tumor-infiltrating lymphocytes of OSCC patients with early or late clinical staging. Moreover, CCR6 Treg cells isolated from tumor-infiltrating lymphocytes or draining lymph nodes maintained similar phenotypic and suppressive characteristics ex vivo as did their counterparts isolated from peripheral blood. These results suggest that CCR6 marks activated effector or memory Treg phenotypes with superior suppressive activity in humans.

Presence of high-endothelial venules correlates with a favorable immune microenvironment in oral squamous cell carcinoma

“…CCL20 attracts cells expressing the CCR6 receptor, such as dendritic cells and memory and effector T cells. Several studies have found that CCL20 is a chief attractant of Treg cells, a distinct lineage of CD4+ T cells that suppresses antitumor immune responses [53][54][55]. Interestingly, tumor cells may also express CCR6, and accordingly, CCL20 has been associated with migration and metastases of cancer cells [56].…”

Perspectives of Immune Suppression in the Tumor Microenvironment Promoting Oral Malignancy

“…Therefore, for the survival of Tregs, an outer supply of IL-2 is essential [ 52 ]. In tumor tissues, many Tregs develop into effector Tregs which express CTLA-4, PD-1 or CCR6 at higher levels, and engage in the disruption of host immune systems including those in OSCC patients [ 53 - 55 ]. The elevated Foxp3 protein expression is a predictive factor for OSCC progression [ 56 ].…”

DNA Methylome Distinguishes Oropharyngeal and Oral Cancer from Oral Lesions and Healthy Oral Mucosa

“…Moreover, in the meta-analysis of Liu et al (48) on patients with cervical carcinoma, CDH1 promoter methylation was signi cantly higher in cancer than in cervical intraepithelial neoplasia lesions and healthy cervical tissues.The rst fteen genes that were signi cantly hypomethylated on different sites across the genome in cancer tissues in comparison to control healthy tissues, ATXN1, PPP2R2C, CCR6, RAB37, DUSP27, ZNF521, SLC6A17, SPIN1, CXCR1, SPTBN1, NBAS, NRG3, COL5A1, CDX1, and BATF3 are mostly involved in transcriptional and immune regulation. Among this group of genes, aberrantly methylated in other human cancers were CCR6 in oral cancer(49) and chronic lymphocytic leukemia (50), RAB37 in lung cancer (51), ZNF521 in breast cancer(52), and CDX1 in gastric cancer(53), esophageal SCC (54) and in colon cancer(55). The genes involved in immune regulation could belong to the tumor-in ltrating immune cells or tumor-in ltrating lymphocytes, which are often associated with better clinical outcomes.…”

“…The genes involved in immune regulation could belong to the tumor-in ltrating immune cells or tumor-in ltrating lymphocytes, which are often associated with better clinical outcomes. Thus, the aberrantly methylated gene CCR6 (C-C Motif Chemokine Receptor 6), which regulates the migration and recruitment of dendritic and T cells during in ammatory and immunological responses, was also found in human OSCC(49). Lee et al(49) concluded that hypomethylation of this gene may play an important role in the recruitment or retention of CCR6 + Treg cells into OSCC in ammatory microenvironment at the early stage of tumor progression.…”

“…Thus, the aberrantly methylated gene CCR6 (C-C Motif Chemokine Receptor 6), which regulates the migration and recruitment of dendritic and T cells during in ammatory and immunological responses, was also found in human OSCC(49). Lee et al(49) concluded that hypomethylation of this gene may play an important role in the recruitment or retention of CCR6 + Treg cells into OSCC in ammatory microenvironment at the early stage of tumor progression. In addition, genome-wide DNA methylation analysis of chronic lymphocytic leukemia patients in comparison to healthy donors identi ed differently methylated CCR6 gene, among other immune regulatory genes(50).…”