Adenosine metabolism of human mesenchymal stromal cells isolated from patients with head and neck squamous cell carcinoma

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• 作者：Patrick J. Schuler^a ; ^b ; ^{patrick.schuler@uniklinik-ulm.de" class="auth_mail" title="E-mail the corresponding author} ; Anna-Maria Westerkamp^a ; ^{amwesterkamp@web.de" class="auth_mail" title="E-mail the corresponding author} ; Benjamin A. Kansy^a ; ^{benjamin.kansy@uk-essen.de" class="auth_mail" title="E-mail the corresponding author} ; Kirsten Bruderek^a ; ^{kirsten.bruderek@uk-essen.de" class="auth_mail" title="E-mail the corresponding author} ; Philip A. Dissmann^a ; ^{philip.dissmann@uk-essen.de" class="auth_mail" title="E-mail the corresponding author} ; Claudia A. Dumitru^a ; ^{claudia.dumitru@uni-due.de" class="auth_mail" title="E-mail the corresponding author} ; Stephan Lang^a ; ^{stephan.lang@uk-essen.de" class="auth_mail" title="E-mail the corresponding author} ; Edwin K. Jackson^c ; ^{edj@pitt.edu" class="auth_mail" title="E-mail the corresponding author} ; Sven Brandau^a ; ^{Sven.Brandau@uk-essen.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ADO ; adenosine ; CFSE ; carboxyfluorescein succinimidyl ester ; HNSCC ; head and neck squamous cell cancer ; HO-1 ; heme oxygenase 1 ; IDO ; indoleamine 2&prime ; 3 dioxygenase ; MSC ; mesenchymal stromal cells ; PBMC ; peripheral blood mononuclear cells ; PGE2 ; prostaglandin E2 ; TCMcMSC ; tumor conditioned medium control MSC ; Treg ; regulatory T-cells
• 刊名：Immunobiology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：222
• 期：1
• 页码：66-74
• 全文大小：2096 K

文摘

Mesenchymal stromal cells (MSC) are a major component of the tumor microenvironment in patients with head and neck squamous cell carcinoma (HNSCC). MSC display innate and regulatory immunologic functions, very similar to many hematopoietic ‘classical’ immune cells. Conversion of ATP to immunosuppressive adenosine is an immunosuppressive mechanism utilized by other hematopoietic immune cells. The present study explores the adenosine metabolism of tumor derived MSC in comparison to autologous MSC from non-malignant tissue.

Methods

From HNSCC patients (n = 10), paired MSC were generated from tumor tissue (tMSC) and autologous healthy control tissue (cMSC). Differentiation properties and phenotype (CD105, CD73, CD39, CD90, CD26, CD29) were compared by flow cytometry. Production of immunosuppressive adenosine (ADO) by functionally active ectonucleotidases, CD39 and CD73, was determined by luminescence and mass spectrometry. Suppressive activity of ADO was tested in CFSE proliferation assays of isolated T-cells. Plasticity of cMSC was explored after incubation with tumor-cell conditioned media.

Results

Differentiation into osteogenic, chondrogenic and adipogenic directions was comparable in tMSC and cMSC. Expression of ectonucleotidases, CD39 and CD73, was decreased in tMSC as compared to corresponding cMSC, which correlated with decreased ATP metabolism in mass spectrometry. Proliferation of CD4⁺ T-cells was significantly suppressed by exogenous ADO. Tumor-conditioned medium was unable to down-regulate ADO production in cMSC.

Conclusion

We identified MSC of the oropharyngeal mucosa as an important producer of exogenous ADO. In patients with HNSCC, reduced expression of ADO may contribute to excessive inflammation and tumor growth.