Research Papers:

The influence of chemotherapy on adenosine-producing B cells in patients with head and neck squamous cell carcinoma

Andreas Ziebart _, Ulrich Huber, Sandra Jeske, Simon Laban, Johannes Doescher, Thomas K. Hoffmann, Cornelia Brunner, Edwin K. Jackson and Patrick J. Schuler

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Oncotarget. 2018; 9:5834-5847. https://doi.org/10.18632/oncotarget.23533

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Andreas Ziebart1,2, Ulrich Huber2, Sandra Jeske2, Simon Laban2, Johannes Doescher2, Thomas K. Hoffmann2, Cornelia Brunner2, Edwin K. Jackson3 and Patrick J. Schuler2

1Department of Neurosurgery, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany

2Department of Otolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany

3Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

Correspondence to:

Patrick J. Schuler, email: [email protected]

Keywords: regulatory B cells; adenosine; head and neck cancer; cisplatin; methotrexate

Received: October 05, 2017     Accepted: December 01, 2017     Published: December 20, 2017


Introduction: Head and neck squamous cell carcinoma (HNSCC) strongly suppresses the immune system, resulting in increased metastasis and recurrent disease. Chemotherapy is part of the multimodal treatment but may further immunosuppression. Recently, we demonstrated that regulatory B cells (Breg), defined as CD19+CD39+CD73+ B cells, play a significant role in the production of immunosuppressive, extracellular adenosine (ADO). Here, we tested the influence of chemotherapy on Breg function.

Results: In HNSCC patients, Breg were diminished in absolute number and frequency after chemotherapy (paired samples). Chemotherapeutic drugs had variable effects; while platinum-based chemotherapy decreased the expression of CD39, methotrexate led to a functional increase in CD39 expression and increased production of immunosuppressive ADO. These findings were confirmed in a second patient cohort. Surface expression of CD39 correlated strongly with the production of ADO as measured by mass spectrometry.

Conclusions: Platinum-based anti-tumor-therapy reduces the number of adenosine-producing B cells and, consequently, potential immunosuppression within the tumor environment. Breg function in terms of ADO production and their potential capacity to suppress CD4+ T cells are promoted by methotrexate treatment amplifying anti-inflammatory therapeutic effects. Our results add to the understanding of how chemotherapeutic drugs can influence the human immune system and may therefore help to orchestrate standard oncologic therapy with new immune modulating approaches.

Methods: Mononuclear cells were collected prospectively from HNSCC patients before and after chemotherapy (n = 18), from healthy donors (n = 20), and an additional cohort sampled several months after chemotherapy (n = 14). Frequency, phenotype, and function of Breg were determined by multicolor flow cytometry, ATP luminescence assay as well as mass spectrometry measuring 5’-AMP, ADO, and inosine. Isolated B cells were incubated with chemotherapeutic drugs (cisplatin, methotrexate, paclitaxel, 5-fluorouracil) in vitro for functional studies.

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