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Preferential recruitment of Th17 cells to cervical cancer via CCR6-CCL20 pathway.

Yu Q, Lou XM, He Y - PLoS ONE (2015)

Bottom Line: However, the source of the increased tumor-infiltrating Th17 cells remains poorly understood.We investigated the prevalence, phenotype and trafficking property of Th17 cells in patients with cervical cancer.In conclusion, Th17 cells are recruited into tumor tissues preferentially through CCR6-CCL20 pathway, which can serve as a novel therapeutic target for cervical cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Hangzhou Obstetrics and Gynecology Hospital, Hangzhou First People's Hospital, Hangzhou, China.

ABSTRACT
Our previous studies suggest that Th17 cells accumulate within tumor tissues and correlate with recurrence of cervical cancer patients. However, the source of the increased tumor-infiltrating Th17 cells remains poorly understood. We investigated the prevalence, phenotype and trafficking property of Th17 cells in patients with cervical cancer. Our results showed that Th17 cells highly aggregated within tumor tissues in an activated phenotype with markedly increased expression of CCR6. Correspondingly, level of CCL20 in the tumor tissues was significantly higher than that in non-tumor and normal control tissues, and strongly positively associated with Th17 cells. Further, in vitro migration assay showed CCL20 had effective chemotaxis to circulating Th17 cells. In conclusion, Th17 cells are recruited into tumor tissues preferentially through CCR6-CCL20 pathway, which can serve as a novel therapeutic target for cervical cancer.

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Chemokine effects on Th17 cell recruitment.Migration assays were performed in a Transwell system. (A) Th17 cells migrate in response to recombinant human CCL17, CCL20 and CCL22 in dose-dependent manner (n = 5). Specific antibodies to chemokines significantly inhibit Th17 cell migration.***P < 0.001. (B and C) Expression of CCL20 by HeLa, Siha, and C-33A cells detected using Real-time PRC (B) and ELISA (C). All the three cervical cells could highly secrete CCL20 with highest level of CCL20 by HeLa cells. (D) Th17 cells also migrate toward culture supernatants of HeLa, Siha, and C-33A cells, which can be efficiently blocked by antibody against CCL20 alone or in combination with CCL17 and CCL22, but significantly less effectively by antibody against CCL17 or CCL22 (n = 3). *P < 0.05, **P < 0.01,***P < 0.001.
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pone.0120855.g005: Chemokine effects on Th17 cell recruitment.Migration assays were performed in a Transwell system. (A) Th17 cells migrate in response to recombinant human CCL17, CCL20 and CCL22 in dose-dependent manner (n = 5). Specific antibodies to chemokines significantly inhibit Th17 cell migration.***P < 0.001. (B and C) Expression of CCL20 by HeLa, Siha, and C-33A cells detected using Real-time PRC (B) and ELISA (C). All the three cervical cells could highly secrete CCL20 with highest level of CCL20 by HeLa cells. (D) Th17 cells also migrate toward culture supernatants of HeLa, Siha, and C-33A cells, which can be efficiently blocked by antibody against CCL20 alone or in combination with CCL17 and CCL22, but significantly less effectively by antibody against CCL17 or CCL22 (n = 3). *P < 0.05, **P < 0.01,***P < 0.001.

Mentions: Significant chemotactic responses of circulating Th17 cells to recombinant human CCL20 were observed in dose-dependent manner (Fig. 5A). Further, a neutralizing monoclonal antibody to CCL20 did markedly blocked CCL20-induced migration of Th17 cells (P < 0.001, Fig. 5A). Though CCL17 and CCL22 can also induce migration of Th17 cells, their effect was significantly weaker than CCL20 did (migration index in concentration of 100 ng/ml: CCL20, 45.5 ± 10.6 vs. CCL17, 19.1 ± 6.5 and vs. CCL22, 26.1 ± 7.9, both P < 0.001; Fig. 5A). To further determine whether tumor-secreted chemokines had an effect on Th17 cell recruitment, chemotaxis assay using culture supernatants from cervical cell lines was performed. The HeLa cells are HPV-18 infected cervical cells, Siha cells are HPV-16 infected cervical cells, and C-33A cells are HPV negative cervical cancer cells. All the three cervical cells could highly secrete CCL20 with highest level of CCL20 by HeLa cells (Fig. 5B and 5C), and induced significant migration of Th17 cells (Fig. 5D). This can be efficiently blocked by antibody against CCL20 alone or in combination with CCL17 and CCL22 (P < 0.001), but significantly less effectively by antibody against CCL17 or CCL22 (Fig. 5B). These results collectively indicate that CCL20 can induce effective migration of Th17 cells into tumor tissues.


Preferential recruitment of Th17 cells to cervical cancer via CCR6-CCL20 pathway.

Yu Q, Lou XM, He Y - PLoS ONE (2015)

Chemokine effects on Th17 cell recruitment.Migration assays were performed in a Transwell system. (A) Th17 cells migrate in response to recombinant human CCL17, CCL20 and CCL22 in dose-dependent manner (n = 5). Specific antibodies to chemokines significantly inhibit Th17 cell migration.***P < 0.001. (B and C) Expression of CCL20 by HeLa, Siha, and C-33A cells detected using Real-time PRC (B) and ELISA (C). All the three cervical cells could highly secrete CCL20 with highest level of CCL20 by HeLa cells. (D) Th17 cells also migrate toward culture supernatants of HeLa, Siha, and C-33A cells, which can be efficiently blocked by antibody against CCL20 alone or in combination with CCL17 and CCL22, but significantly less effectively by antibody against CCL17 or CCL22 (n = 3). *P < 0.05, **P < 0.01,***P < 0.001.
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pone.0120855.g005: Chemokine effects on Th17 cell recruitment.Migration assays were performed in a Transwell system. (A) Th17 cells migrate in response to recombinant human CCL17, CCL20 and CCL22 in dose-dependent manner (n = 5). Specific antibodies to chemokines significantly inhibit Th17 cell migration.***P < 0.001. (B and C) Expression of CCL20 by HeLa, Siha, and C-33A cells detected using Real-time PRC (B) and ELISA (C). All the three cervical cells could highly secrete CCL20 with highest level of CCL20 by HeLa cells. (D) Th17 cells also migrate toward culture supernatants of HeLa, Siha, and C-33A cells, which can be efficiently blocked by antibody against CCL20 alone or in combination with CCL17 and CCL22, but significantly less effectively by antibody against CCL17 or CCL22 (n = 3). *P < 0.05, **P < 0.01,***P < 0.001.
Mentions: Significant chemotactic responses of circulating Th17 cells to recombinant human CCL20 were observed in dose-dependent manner (Fig. 5A). Further, a neutralizing monoclonal antibody to CCL20 did markedly blocked CCL20-induced migration of Th17 cells (P < 0.001, Fig. 5A). Though CCL17 and CCL22 can also induce migration of Th17 cells, their effect was significantly weaker than CCL20 did (migration index in concentration of 100 ng/ml: CCL20, 45.5 ± 10.6 vs. CCL17, 19.1 ± 6.5 and vs. CCL22, 26.1 ± 7.9, both P < 0.001; Fig. 5A). To further determine whether tumor-secreted chemokines had an effect on Th17 cell recruitment, chemotaxis assay using culture supernatants from cervical cell lines was performed. The HeLa cells are HPV-18 infected cervical cells, Siha cells are HPV-16 infected cervical cells, and C-33A cells are HPV negative cervical cancer cells. All the three cervical cells could highly secrete CCL20 with highest level of CCL20 by HeLa cells (Fig. 5B and 5C), and induced significant migration of Th17 cells (Fig. 5D). This can be efficiently blocked by antibody against CCL20 alone or in combination with CCL17 and CCL22 (P < 0.001), but significantly less effectively by antibody against CCL17 or CCL22 (Fig. 5B). These results collectively indicate that CCL20 can induce effective migration of Th17 cells into tumor tissues.

Bottom Line: However, the source of the increased tumor-infiltrating Th17 cells remains poorly understood.We investigated the prevalence, phenotype and trafficking property of Th17 cells in patients with cervical cancer.In conclusion, Th17 cells are recruited into tumor tissues preferentially through CCR6-CCL20 pathway, which can serve as a novel therapeutic target for cervical cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Hangzhou Obstetrics and Gynecology Hospital, Hangzhou First People's Hospital, Hangzhou, China.

ABSTRACT
Our previous studies suggest that Th17 cells accumulate within tumor tissues and correlate with recurrence of cervical cancer patients. However, the source of the increased tumor-infiltrating Th17 cells remains poorly understood. We investigated the prevalence, phenotype and trafficking property of Th17 cells in patients with cervical cancer. Our results showed that Th17 cells highly aggregated within tumor tissues in an activated phenotype with markedly increased expression of CCR6. Correspondingly, level of CCL20 in the tumor tissues was significantly higher than that in non-tumor and normal control tissues, and strongly positively associated with Th17 cells. Further, in vitro migration assay showed CCL20 had effective chemotaxis to circulating Th17 cells. In conclusion, Th17 cells are recruited into tumor tissues preferentially through CCR6-CCL20 pathway, which can serve as a novel therapeutic target for cervical cancer.

Show MeSH
Related in: MedlinePlus