Abstract
IntroductionHead 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.ResultsIn 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.ConclusionsPlatinum-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.MethodsMononuclear 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.
Highlights
Head and neck squamous cell carcinoma (HNSCC) strongly suppresses the immune system, resulting in increased metastasis and recurrent disease
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
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
Summary
Head and neck squamous cell carcinoma (HNSCC) strongly suppresses the immune system, resulting in increased metastasis and recurrent disease. It has been suggested that the relevance of TIL-B as a prognostic marker may exceed the role of CD8+ T lymphocytes, given that the interaction of both cell types is mandatory for a sufficient anti-tumor response [5] Their controversial function includes a tumorpromoting role [6] and several murine tumor models implement a pro-tumor effect of TIL-B [7, 8]. B cells inhibit the anti-tumor effect of vaccination against murine malignant melanoma and they induce radioresistance in murine prostate cancer [9, 10] This effect may be partly explained by conversion and attraction of regulatory T cells (Treg) into the tumor micro-environment [1]. It reiterates the difficulty in correlating murine models with the human system
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