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Published on: February 8, 2022
CDX2 enhances natural killer cell-mediated immunotherapy against head and neck squamous cell carcinoma through
Haitao Wang1, Shanji Nan2, Ying Wang3
1Department of Otolaryngology Head and Neck Surgery, Jilin University Second Hospital, Changchun, China.
Abstract:
(NK) cells are at the first line of defence against tumours, but their anti-tumour mechanisms are not fully understood. We aimed to investigate the mechanism by which NK cells can mediate immunotherapy against head and neck squamous cell carcinoma (HNSCC). We collected fifty-two pairs of HNSCC tissues and corresponding adjacent normal tissues; analysis by RT-qPCR showed underexpression of CXCL14 in HNSCC tissues. Primary NK cells were then isolated from the peripheral blood of HNSCC patients and healthy donors. CXCL14 was found to be consistently under-expressed in the primary NK cells from the HNSCC patients. However, CXCL14 expression was increased in IL2-activated primary NK cells and NK-92 cells. We next evaluated NK cell migration, IFN-γ and TNF-α expression, cytotoxicity and infiltration in response to CXCL14 overexpression or knockdown using gain- and loss-of-function approach. The results exhibited that CXCL14 overexpression promoted NK cell migration, cytotoxicity and infiltration. Subsequent in vivo experiments revealed that CXCL14 suppressed the growth of HNSCC cells via activation of NK cells. ChIP was applied to study the enrichment of H3K27ac, p300, H3K4me1 and CDX2 in the enhancer region of CXCL14, which showed that CDX2/p300 activated the enhancer of CXCL14 to up-regulate its expression. Rescue experiments demonstrated that CDX2 stimulated NK cell migration, cytotoxicity and infiltration through up-regulating CXCL14. In vivo data further revealed that CDX2 suppressed tumorigenicity of HNSCC cells through enhancement of CXCL14. To conclude, CDX2 promotes CXCL14 expression by activating its enhancer, which promotes NK cell-mediated immunotherapy against HNSCC.
Insights
The transcription factor CDX2 enhances Natural Killer (NK) cell immunotherapy against head and neck squamous cell carcinoma (HNSCC) by upregulating CXCL14 expression, thereby improving NK cell anti-tumor functions.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Natural Killer (NK) cells are crucial for early anti-tumor defense, but their precise mechanisms against head and neck squamous cell carcinoma (HNSCC) require further elucidation.
- CXCL14 is frequently underexpressed in HNSCC tissues and NK cells from HNSCC patients, suggesting a potential role in tumor immune evasion.
Purpose of the Study:
- To investigate the role of CXCL14 in NK cell-mediated immunotherapy against HNSCC.
- To identify the regulatory mechanism of CXCL14 expression and its impact on NK cell functions.
- To explore the therapeutic potential of targeting the CDX2-CXCL14 axis in HNSCC.
Main Methods:
- Analysis of CXCL14 expression in HNSCC tissues and primary NK cells using RT-qPCR.
- In vitro gain- and loss-of-function studies to assess the effects of CXCL14 on NK cell migration, cytotoxicity, and cytokine production (IFN-γ, TNF-α).
- Chromatin immunoprecipitation (ChIP) assays to investigate the regulatory elements and transcription factors involved in CXCL14 gene activation, including CDX2 and p300.
- In vivo experiments using HNSCC models to evaluate the anti-tumor efficacy of CXCL14 and CDX2 modulation.
Main Results:
- CXCL14 was significantly underexpressed in HNSCC tissues and primary NK cells from HNSCC patients, but its expression increased upon IL-2 activation.
- Overexpression of CXCL14 enhanced NK cell migration, cytotoxicity, and infiltration, while knockdown impaired these functions.
- CDX2, in conjunction with p300, was identified as a key transcription factor that activates the enhancer region of CXCL14, leading to its upregulation.
- Both in vitro and in vivo studies demonstrated that CDX2 promotes NK cell-mediated anti-tumor activity against HNSCC by upregulating CXCL14.
Conclusions:
- CDX2 acts as a crucial regulator of CXCL14 expression by activating its enhancer region.
- Upregulation of CXCL14 by CDX2 significantly enhances NK cell functions, including migration, cytotoxicity, and infiltration.
- The CDX2-CXCL14 axis represents a promising therapeutic target for augmenting NK cell-based immunotherapy in head and neck squamous cell carcinoma.
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