Abstract 3653: Enrichment of Foxp3+ CD4 Tregs in migrated T-cells to IL-6- and IL-8-expressing tumors through predominant induction of CXCR1 by IL-6
Authors: Eikawa Shingo , Ohue Yoshihiro , Kitaoka Kenta , Aji Toshiki , Uenaka Akiko , Isobe Midori , Oka Mikio , Nakayama Eiichi 
Published: June 2012

Background: Analysis of cytokine and chemokine production by tumor cell lines including 5 lung cancers, a malignant mesothelioma and a malignant melanoma recently established in our laboratory showed rather high production of IL-8 in all tumors and IL-6 in one lung cancer, the malignant mesothelioma and the malignant melanoma. We investigated migration of PBMCs to these tumor cells using Transwell plates and showed enrichment of Foxp3+ CD4 Tregs in migrated T-cells to both IL-6- and IL-8-producing tumors. Marked induction of CXCR1 expression on Foxp3+ CD4 Tregs by IL-6 followed by IL-8-mediated migration appeared to be the mechanisms for enriched migration. Frequent production of IL-8 by the tumors and Treg migration to those tumors through induction of IL-8 receptor expression by IL-6 is one of the mechanisms for tumor escape.

Purpose: In this study, we investigated cytokine and chemokine production by tumor cell lines including 5 lung cancers, a malignant mesothelioma and a malignant melanoma recently established in our laboratory. We observed IL-8 production in all tumors and IL-6 production in one lung cancer, a malignant mesothelioma and a malignant melanoma. We investigated migration of Foxp3+ CD4 Tregs in PBMCs to those tumor cells using Transwell plates.

Experimental Design: Cytokine and chemokine production was analyzed in tumor cell lines including 5 lung cancers, a malignant mesothelioma and a malignant melanoma recently established in our laboratory. IL-8 production was detected in all tumors and IL-6 production in 3 of them. We then investigated the role of IL-6 and IL-8 on migration of Foxp3+ CD4 Tregs to those tumor cells using Transwell plates. Induction of IL-8 receptor on Foxp3+ CD4 T-cells by IL-6 was investigated by flow cytometry and its role on their migration was examined by anti-IL-8R or anti-IL-6R blocking. Furthermore, to investigate relationships between the effect of IL-6 and STAT3 signaling in the induction of IL-8R expression, we examined whether IL-8R expression would inhibit by blocking of STAT3 signaling.

Results: We showed enrichment of Foxp3+ CD4 Tregs in migrated T-cells to both IL-6 and IL-8-producing tumors. Marked induction of CXCR1 (IL-8RA) expression was observed on Foxp3+ CD4 Tregs by the treatment with IL-6. Migration of IL-6-treated Foxp3+ CD4 T-cells to the tumors was blocked by the addition of anti-CXCR1 or anti-IL-6R. Furthermore, high level of IL-6 was detected in pleural effusion in most of lung cancer patients.Conclusions: Frequent production of IL-8 by the tumors and Treg migration to those tumors through induction of IL-8 receptor expression by IL-6 is one of the mechanisms for tumor escape. The findings indicate that the blocking of Treg migration by inhibiting IL-6-mediated IL-8 receptor expression could be a new strategy for tumor immunotherapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3653. doi:10.1158/1538-7445.AM2011-3653