Local Effects of Regulatory T Cells in MUC1 Transgenic Mice Potentiate Growth of MUC1 Expressing Tumor Cells In Vivo

Daisuke Sugiura,Kazuyoshi Takeda,Mitsuyo Takashima,Kaori Denda-Nagai,Tatsuro Irimura,Shigenori Nagai,Ryuichi Murakami,Nupur Gangopadhyay

doi:10.1371/journal.pone.0044770

Daisuke Sugiura, Kazuyoshi Takeda + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0044770

Copy DOI

Abstract

MUC1 transgenic (MUC1.Tg) mice have widely been used as model recipients of cancer immunotherapy with MUC1. Although MUC1.Tg mice have previously been shown to be immunologically tolerant to MUC1, the involvement of regulatory T (Treg) cells in this phenotype remains unclear. Here, we showed that numbers of Treg cells in MUC1-expressing tumors were greater in MUC1.Tg mice than in control C57BL/6 (B6) mice, and that the growth of tumor cells expressing MUC1, but not that of control cells, in MUC1. Tg mice was faster than in B6 mice. The MUC1.Tg mice appeared to develop MUC1-specific peripheral tolerance, as transferred MUC1-specific T cells were unable to function in MUC1.Tg mice but were functional in control B6 mice. The suppressive function of CD4+CD25high cells from MUC1.Tg mice was more potent than that of cells from control B6 mice when Treg cell activity against MUC1-specific T cells was compared in vitro. Therefore, the enhanced growth of MUC1-expressing tumor cells in MUC1.Tg mice is likely due to the presence of MUC1-specific Treg cells.

Highlights

The immune system suppresses or enhances the growth of malignant cells in a variety of ways
The weight of cecum induced by SL4-MUC1 cells was heavier when the cells were injected into MUC1.Tg mice than when they were injected into B6 mice (Fig. 1), suggesting that the growth of MUC1-positive tumor cells was enhanced in MUC1.Tg mice
The survival curves were very similar to those of mice injected with control T cells. These results clearly indicate that MUC1.Tg mice develop MUC1-spcific peripheral tolerance possibly mediated by Treg cells, and this tolerance mechanism is involved in the escape of tumor cells from elimination by specific T cells

Summary

Introduction

The immune system suppresses or enhances the growth of malignant cells in a variety of ways. In contrast to the known anti-tumor effector functions mediated by tumor antigen-specific T cells, regulatory T (Treg) cells, consisting of a subpopulation of CD4+ T cells, are known to be involved in the establishment and growth of tumor cells [1]. There are many reports showing that the depletion of Treg cells or neutralization of Treg cell-associated molecules suppresses tumor growth in vivo [4]. These results clearly demonstrate that Treg cells suppress anti-tumor immune responses and enhance tumor growth. Whether Treg cells recognize a specific tumor antigen and suppress tumor antigen-specific immune responses is an important issue to further understand the involvement of Treg cells in tumor immunity. There are only few reports focusing on clinically relevant and well-characterized tumor-antigens or on animal models with natural variations of TCRs [8,9]

Methods

Results

Conclusion