Abstract 1915: Enrichment of Tregs in migrated T-cells to IL-6- and IL-8-expressing tumors through induction of CXCR1 by IL-6
Authors: Eikawa Shingo , Ohue Yoshihiro , Kitaoka Kenta , Aji Toshiki , Uenaka Akiko , Oka Mikio , Nakayama Eiichi 
Published: February 2011

Background: Several mechanisms by which tumors evade the host immune response have been elucidated. A tumor modulates its antigenicity by immunoediting during development of an overt tumor, and frequently loses MHC and/or tumor antigen expression. Recently, it has been shown that regulatory T-cells were closely involved in immune impairment against tumors. Naturally occurring Foxp3+ CD25 high CD4 Tregs were observed in local tumor sites in some ovarian cancer patients and infiltration of those Tregs in the tumor correlated well with poor patient prognosis. Moreover, recently, an increase in the number of Tregs in the peripheral blood has been shown in advanced cancer patients and immune down-regulation systemically occurring in those patients is one cause of the ineffectiveness of immunization in clinical trials using cancer vaccines. The evidence suggests that it is necessary to regulate Tregs function and their accumulation to tumor local site for induction of effective immune response against tumors.

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 blocking.

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. In fact, 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 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1915.