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Netrin-1 Promotes the Immunosuppressive Activity of MDSCs in Colorectal Cancer
Xueli Xia1,2, Zhenwei Mao2,3, Wenxin Wang2
1Department of General Surgery, Affiliated Hospital of Jiangsu University, Institute of Digestive Diseases, Jiangsu University. Zhenjiang, China.
Abstract:
Myeloid-derived suppressive cells (MDSC) inhibit antitumor immunity and confer a survival advantage for tumor evasion. Tumor cells also support MDSC expansion and recruitment by secreting multiple growth factors and cytokines, but the mechanisms by which tumors affect MDSC function are not completely understood. Here, we found that the neuronal guidance protein netrin-1 was selectively secreted by MC38 murine colon cancer cells, which could enhance the immunosuppressive activity of MDSCs. MDSCs predominantly expressed one type of netrin-1 receptor, adenosine receptor 2B (A2BR). Netrin-1 interacted with A2BR on MDSCs to activate the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway, which ultimately increased CREB phosphorylation in MDSCs. Furthermore, netrin-1 knockdown in tumor cells inhibited the immunosuppressive activity of MDSCs and restored antitumor immunity in MC38 tumor xenograft mice. Intriguingly, high netrin-1 in the plasma correlated with MDSCs in patients with colorectal cancer. In conclusion, netrin-1 significantly enhanced the immunosuppressive function of MDSCs through A2BR on MDSCs, thus promoting the development of tumors. These findings highlight that netrin-1 may regulate the abnormal immune response in colorectal cancer and may become a potential target for immunotherapy.
Insights
Netrin-1 secreted by colon cancer cells enhances immunosuppressive myeloid-derived suppressive cells (MDSCs) via A2BR signaling. Targeting netrin-1 may restore antitumor immunity and offer a new immunotherapy strategy for colorectal cancer.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Myeloid-derived suppressive cells (MDSCs) are crucial for tumor immune evasion.
- Tumor cells secrete factors that promote MDSC expansion and recruitment.
- Mechanisms by which tumors influence MDSC function require further elucidation.
Purpose of the Study:
- To investigate the role of netrin-1 in modulating MDSC function in colorectal cancer.
- To identify the receptor and signaling pathway involved in netrin-1-mediated MDSC activation.
- To evaluate the therapeutic potential of targeting netrin-1 in a preclinical model.
Main Methods:
- Analysis of netrin-1 secretion by MC38 colon cancer cells.
- Assessment of MDSC receptor expression and netrin-1 interaction.
- Investigation of the cAMP/PKA/CREB signaling pathway activation in MDSCs.
- Tumor xenograft studies with netrin-1 knockdown in tumor cells.
- Correlation analysis of plasma netrin-1 and MDSC levels in colorectal cancer patients.
Main Results:
- Netrin-1 is selectively secreted by MC38 colon cancer cells and enhances MDSC immunosuppressive activity.
- MDSCs express adenosine receptor 2B (A2BR), which binds netrin-1.
- Netrin-1 activates the cAMP/PKA pathway, leading to CREB phosphorylation in MDSCs.
- Netrin-1 knockdown in tumors inhibited MDSC immunosuppression and restored antitumor immunity.
- Elevated plasma netrin-1 levels correlated with MDSC presence in colorectal cancer patients.
Conclusions:
- Netrin-1 promotes tumor development by enhancing MDSC immunosuppressive function via A2BR signaling.
- Netrin-1 represents a potential therapeutic target for colorectal cancer immunotherapy.
- Netrin-1 may play a significant role in regulating the immune response in colorectal cancer.
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