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Published on: July 20, 2019
NME4 suppresses NFκB2-CCL5 axis, restricting CD8+ T cell tumour infiltration in oesophageal squamous cell carcinoma
Shutao Zheng1, Shuo He1, Yan Liang1
1State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China.
Abstract:
Thought of as a metastasis-associated gene, however, NME/NM23 nucleoside diphosphate kinase 4 (NME4) has rarely been described in the context of the tumour microenvironment. To understand the immunological implications of NME4 in oesophageal squamous cell carcinoma (ESCC), we used multiplex immunohistochemistry to analyse the clinicopathological and prognostic importance of NME4 expression. Then, after establishing a syngeneic tumour model with a C57BL/6 mouse strain that can recapitulate the tumour microenvironment of humans, we examined the immunological involvement of NME4 expression. To explore the underlying molecular mechanism, via quantitative proteomics and protein microarray screening, we investigated the potential signalling pathways involved. The clinicopathological and prognostic importance of NME4 expression is limited in ESCC patients. In vivo, single-cell RNA sequencing showed that NME4 strikingly prevented CD8+ T cells from infiltrating the tumour microenvironment in murine ESCC. Mechanistically, we mapped out the NFκB2-CCL5 axis that was negatively controlled by NME4 in the murine ESCC cell line AKR. Collectively, these data demonstrated that regulation of NFκB2-CCL5 axis by NME4 prevents CD8+ T cells infiltration in ESCC.
Insights
NME4, a metastasis-associated gene, hinders CD8+ T cell infiltration in oesophageal squamous cell carcinoma (ESCC) by regulating the NFκB2-CCL5 axis, impacting the tumor microenvironment.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- NME/NM23 nucleoside diphosphate kinase 4 (NME4) is recognized as a metastasis-associated gene.
- Its role within the tumor microenvironment, particularly in oesophageal squamous cell carcinoma (ESCC), remains underexplored.
Purpose of the Study:
- To investigate the immunological implications of NME4 expression in ESCC.
- To elucidate the molecular mechanisms underlying NME4's function in the tumor microenvironment.
Main Methods:
- Multiplex immunohistochemistry was employed to assess NME4 expression in ESCC patients.
- A syngeneic murine ESCC model (C57BL/6) was established for in vivo studies.
- Single-cell RNA sequencing, quantitative proteomics, and protein microarray screening were utilized to explore molecular pathways.
Main Results:
- NME4 expression showed limited clinicopathological and prognostic significance in human ESCC.
- In vivo, NME4 significantly inhibited CD8+ T cell infiltration into the tumor microenvironment of murine ESCC.
- The NFκB2-CCL5 signaling axis was identified as a key pathway negatively regulated by NME4.
Conclusions:
- NME4 plays a critical role in preventing CD8+ T cell infiltration in ESCC.
- The mechanism involves NME4's regulation of the NFκB2-CCL5 axis, impacting the tumor immune microenvironment.
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