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Implication of IZUMO2 in the cell-in-cell phenomenon: A potential therapeutic target for triple-negative breast
Toshiya Higashi1, Chiemi Saigo2,3,4, Wakana Chikaishi1
1Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Japan.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
The findings highlight the importance of IZUMO2 on TNBC cells in facilitating the cell-in-cell phenomenon by A-Tregs.
Insights
Researchers identified IZUMO2 as a key molecule enabling triple-negative breast cancer (TNBC) cells to engulf adiponectin-expressing regulatory T cells (A-Tregs). This discovery offers a new target for TNBC therapies by blocking this interaction.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Triple-negative breast cancer (TNBC) presents aggressive features and resistance to current treatments, necessitating novel therapeutic strategies.
- Adiponectin-expressing regulatory T cells (A-Tregs) induce apoptosis in TNBC via the cell-in-cell phenomenon.
- Identifying the specific molecule mediating TNBC engulfment of A-Tregs is crucial for therapeutic development.
Purpose of the Study:
- To elucidate the molecule responsible for the engulfment of A-Tregs by TNBC cells.
- To develop a therapeutic strategy targeting this interaction to enhance TNBC apoptosis.
Main Methods:
- Development of a monoclonal antibody (G1D7) to inhibit A-Treg engulfment by TNBC.
- Utilized immunoprecipitation, mass spectrometry, and siRNA-mediated gene silencing for antigen characterization.
Main Results:
- The monoclonal antibody G1D7 successfully abrogated A-Treg engulfment by TNBC cells, leading to reduced A-Treg-mediated apoptosis.
- G1D7 identified immunoglobulin-like type I membrane protein IZUMO2 as the target molecule on TNBC cells.
- IZUMO2 is homologous to IZUMO1, a protein critical for sperm-oocyte membrane fusion.
Conclusions:
- IZUMO2 on TNBC cells plays a significant role in facilitating the cell-in-cell phenomenon mediated by A-Tregs.
- Targeting IZUMO2 presents a promising therapeutic avenue for treating triple-negative breast cancer.
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