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Published on: July 25, 2011
Targeting the DKK1/CSF1 signaling axis to reprogram M2 macrophages and reverse chemoresistance in head and neck
Chin-Sheng Huang1, Chih-Ming Huang2, Hang Huong Ling3
1Department of Dentistry, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan; School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei City 110, Taiwan; Department of Dentistry and Oral Health, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan.
Background:
Understanding the mechanisms underlying drug resistance in head and neck squamous cell carcinoma (HNSCC) is critical for the development of effective therapeutic strategies. M2-type tumor-associated macrophages (M2-TAMs), activated by colony-stimulating factor 1 (CSF1), play a pivotal role in promoting chemoresistance and metastasis through immunosuppressive signaling and tumor-immune crosstalk. However, the precise mechanisms of CSF1-driven tumor support and macrophage activation remain incompletely understood.
Methods:
We employed humanized patient-derived xenograft (PDX) models of drug-resistant HNSCC to examine the functional roles of CSF1 and its downstream effectors. Drug-tolerant persister (DTP) cells derived from these models were subjected to transcriptomic profiling. In vitro, both direct and indirect co-culture systems were used to assess the impact of CSF1 modulation on tumor cell viability and M2 macrophage activity. The therapeutic potential of the CSF1R inhibitor pexidartinib (PLX3397), alone and in combination with cisplatin, was evaluated in vivo.
Results:
Our findings revealed that CSF1 silencing in M2 macrophages reduced the viability of cisplatin-resistant SCC9-P and HSC3-P cells in an indirect co-culture system, indicating a paracrine survival signal. In contrast, CSF1 overexpression enhanced tumor cell proliferation. In direct co-culture, CSF1 silencing inhibited M2 macrophage activation, whereas CSF1 overexpression promoted M2 proliferation and immunosuppressive activity. In vivo, pexidartinib effectively disrupted CSF1-mediated resistance and reduced the expression of key tumor-promoting factors, including DKK1, IL10, CXCL12, and AKT1. Clinically, high DKK1 and CSF1 expression correlated with cisplatin resistance and poor prognosis.
Conclusion:
This study underscores the dual role of CSF1 in regulating both tumor survival and M2 macrophage activation in HNSCC. Targeting the DKK1/CSF1 axis may represent a promising strategy to overcome chemoresistance by disrupting tumor-macrophage crosstalk and reprogramming the immunosuppressive microenvironment.
Insights
Colony-stimulating factor 1 (CSF1) drives drug resistance in head and neck squamous cell carcinoma (HNSCC) by supporting tumor cell survival and activating immunosuppressive M2 macrophages. Targeting the DKK1/CSF1 axis offers a potential strategy to overcome chemoresistance.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Drug resistance in head and neck squamous cell carcinoma (HNSCC) remains a significant clinical challenge.
- M2-type tumor-associated macrophages (M2-TAMs), activated by colony-stimulating factor 1 (CSF1), are implicated in promoting chemoresistance and metastasis in HNSCC.
- The precise mechanisms of CSF1-driven tumor support and M2 macrophage activation in HNSCC are not fully elucidated.
Purpose of the Study:
- To investigate the functional roles of CSF1 and its downstream effectors in drug-resistant HNSCC.
- To evaluate the therapeutic potential of targeting the CSF1/CSF1R pathway in HNSCC models.
Main Methods:
- Utilized humanized patient-derived xenograft (PDX) models of drug-resistant HNSCC.
- Performed transcriptomic profiling of drug-tolerant persister (DTP) cells.
- Employed in vitro co-culture systems to assess CSF1 modulation effects on tumor cells and M2 macrophages.
- Evaluated the in vivo efficacy of the CSF1R inhibitor pexidartinib (PLX3397) alone and with cisplatin.
Main Results:
- CSF1 silencing in M2 macrophages reduced cisplatin-resistant HNSCC cell viability, indicating a paracrine survival signal.
- CSF1 overexpression enhanced tumor cell proliferation and M2 macrophage immunosuppressive activity.
- In vivo, pexidartinib disrupted CSF1-mediated resistance and reduced key tumor-promoting factors (DKK1, IL10, CXCL12, AKT1).
- High DKK1 and CSF1 expression correlated with cisplatin resistance and poor prognosis in HNSCC patients.
Conclusions:
- CSF1 plays a dual role in regulating HNSCC tumor survival and M2 macrophage activation.
- Targeting the DKK1/CSF1 axis presents a promising therapeutic strategy to overcome chemoresistance in HNSCC.
- Disrupting tumor-macrophage crosstalk via CSF1 inhibition may reprogram the immunosuppressive tumor microenvironment.
