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The AXL-mediated modulation of myeloid-derived suppressor cells (MDSC) in nasopharyngeal carcinoma
Yu Lv1, Jiahui Zhu1, Sichen Ge1
1Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233000, Anhui, China.
Abstract:
AXL has ubiquitous expression in multiple cancers, and is strongly linked to both tumor progression, metastasis, and poor prognosis, as well as anti-tumor immune response suppression and induction of tumor resistance to immunotherapy. Therefore, it is a strong target for cancer intervention. Despite the wide application of AXL inhibitors in clinical trials, the role of AXL in the tumor immune microenvironment (TIME) remains undetermined. Herein, we established cell lines with stable AXL knockdown or overexpression using lentiviral infection. Subsequently, we co-cultured the cells with healthy human blood-derived CD33 + PBMCs. After two days of culture, we evaluated the differentiation of PBMCs into MDSCs. Additionally, the culture supernatants were collected from both the co-culture system and the individual cultures of each cell group to measure the concentrations of IL-6 and GM-CSF. Additionally, we subcutaneously administered nasopharyngeal carcinoma (NPC) cells into mice, and evaluated the association between AXL content and MDSC recruitment in the resulting tumors. We demonstrated that AXL is a critical modulator of MDSC differentiation and accumulation in NPC. It modulates IL-6, GM-CSF, and Toll-like receptor contents to achieve the aforementioned actions. Herein, we revealed a strong and direct link between AXL, cytokines in TIME, and MDSC differentiation and accumulation. Our work highlights novel approaches to optimizing existing immunotherapeutic interventions.
Insights
AXL receptor tyrosine kinase drives cancer progression and immune suppression. This study reveals AXL critically modulates myeloid-derived suppressor cells (MDSCs) in nasopharyngeal carcinoma, offering new immunotherapy targets.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- AXL receptor tyrosine kinase is implicated in cancer progression, metastasis, and immunotherapy resistance.
- The precise role of AXL in the tumor immune microenvironment (TIME) and its impact on immune cells remains unclear.
Purpose of the Study:
- To investigate the role of AXL in myeloid-derived suppressor cell (MDSC) differentiation and accumulation within the tumor immune microenvironment.
- To elucidate the mechanisms by which AXL influences cytokine production and immune cell populations in nasopharyngeal carcinoma (NPC).
Main Methods:
- Established AXL knockdown and overexpression cell lines via lentiviral infection.
- Co-cultured cancer cells with peripheral blood mononuclear cells (PBMCs) to assess MDSC differentiation.
- Measured cytokine levels (IL-6, GM-CSF) in culture supernatants.
- Evaluated AXL expression and MDSC recruitment in murine NPC models.
Main Results:
- AXL was identified as a critical regulator of MDSC differentiation and accumulation in NPC.
- AXL modulates the TIME by influencing IL-6, GM-CSF, and Toll-like receptor levels.
- A direct correlation was observed between AXL expression and MDSC recruitment in tumors.
Conclusions:
- AXL plays a significant role in shaping the tumor immune microenvironment by controlling MDSC populations.
- Targeting AXL presents a promising strategy for enhancing the efficacy of current cancer immunotherapies.
- Understanding AXL's function in MDSC regulation offers novel therapeutic avenues for NPC and potentially other cancers.
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