Implication of IZUMO2 in the cell-in-cell phenomenon: A potential therapeutic target for triple-negative breast cancer.

Abstract

Triple-negative breast cancer (TNBC) is characterized by the loss of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The aggressive clinicopathological features and resistance to currently available therapeutics of the disease warrant an urgent need for the development of novel alternate therapeutic options. We have previously reported adiponectin-expressing regulatory T cells (A-Tregs), which can induce apoptosis in TNBC through the cell-in-cell phenomenon. In this study, we aimed to elucidate the molecule that allows TNBC cells to engulf A-Tregs. A monoclonal antibody, which repressed the engulfment of A-Tregs by TNBC cells, was developed. Immunoprecipitation followed by mass spectrometry and small interfering RNAs-mediated gene silencing was performed to characterize the antigen. We successfully generated a monoclonal antibody, designated G1D7, which abrogated the engulfment of A-Tregs by TNBC and subsequent A-Treg-mediated apoptosis. G1D7 detected the immunoglobulin-like type I membrane protein IZUMO2, a molecule related to IZUMO1 that is essential for cell-cell membrane binding and fusion of sperm to oocyte. The findings highlight the importance of IZUMO2 on TNBC cells in facilitating the cell-in-cell phenomenon by A-Tregs.