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Updated: Jun 3, 2025
Microfluidic Co-Culture Models for Dissecting the Immune Response in in vitro Tumor Microenvironments
Published on: April 30, 2021
Rbfox3 Promotes Transformation of MDSC-Like Tumor Cells to Shape Immunosuppressive Microenvironment
Zhiyang Li1,2, Zhuangzhuang Feng1, Mengzhan Chen1
1State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 300450, China.
Abstract:
Myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME) contribute to the malignant progression of tumors by exerting immunosuppressive effects. Bacterial lipopolysaccharides (LPS) have been widely demonstrated in various types of solid tumors. LPS can promote the malignant progression of tumors, which mechanism has not yet been fully elucidated. In this study, a type of MDSC-like tumor cells (MLTCs) is found in tumor tissues induced by low-dose and long-term LPS stimulation. MLTCs can simultaneously express tumor cell and MDSCs markers. Similar to MDSCs, MLTCs can produce arginine, nitric oxide, and reactive oxygen species and inhibit the activity of NK and T cells to promote the formation of an immunosuppressive microenvironment. MLTCs can also promote tumor cell proliferation and vasculogenic mimicry formation. CRISPR-Cas9 activity screening studies identified RNA-binding Fox-1 homolog 3 (Rbfox3) as a critical protein for MLTCs formation after LPS treatment. Rbfox3 can transcriptionally regulate the expression of Ass1 in the form of phase-separated particles. Crocin can inhibit the generation of MLTCs by disrupting phase-separated particles of Rbfox3 and enhance the anti-tumor effects of immune checkpoint inhibitors (ICIs).
Insights
Bacterial lipopolysaccharides (LPS) can induce myeloid-derived suppressor cell-like tumor cells (MLTCs) that promote tumor growth and immunosuppression. The protein Rbfox3 is crucial for MLTC formation, and crocin can inhibit this process, enhancing anti-cancer immunity.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) promote tumor progression via immunosuppression.
- Bacterial lipopolysaccharides (LPS) are found in solid tumors and implicated in malignant progression, but mechanisms remain unclear.
Purpose of the Study:
- To investigate the mechanism by which LPS promotes tumor malignant progression.
- To identify novel therapeutic targets for enhancing anti-tumor immunity.
Main Methods:
- Induction of MDSC-like tumor cells (MLTCs) using low-dose, long-term LPS stimulation.
- CRISPR-Cas9 activity screening to identify key proteins in MLTC formation.
- Analysis of Rbfox3's role in regulating Ass1 expression via phase-separated particles.
- Evaluation of crocin's effect on MLTCs and its synergy with immune checkpoint inhibitors (ICIs).
Main Results:
- A novel cell type, MLTCs, was identified, expressing both tumor and MDSC markers.
- MLTCs exhibit immunosuppressive functions, inhibit NK and T cell activity, and promote tumor proliferation and vasculogenic mimicry.
- CRISPR screening identified Rbfox3 as essential for LPS-induced MLTC formation.
- Rbfox3 regulates Ass1 expression through phase-separated particles; crocin disrupts these particles, inhibiting MLTC generation.
Conclusions:
- LPS can induce MLTCs that contribute to tumor progression and immunosuppression.
- Rbfox3 is a key regulator of MLTC formation, acting via phase-separated particles to control Ass1 expression.
- Crocin shows potential as a therapeutic agent to inhibit MLTCs and enhance the efficacy of ICIs in cancer treatment.
