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Adenosine-producing regulatory B cells in head and neck cancer.

ABSTRACT: BACKGROUND:Multiple mechanisms of immunosuppression have been identified in the tumor microenvironment including regulatory B cells (Breg). Recently, we have shown that Breg suppress T cell function by production of adenosine (ADO). However, the autocrine effect of ADO on B cells and the role of Breg in head and neck cancer remains unclear. METHODS:Blood (n?=?42) and tumor tissue (n?=?39) of head and neck cancer patients and healthy donors (n?=?60) were analyzed by FACS. The effect of ADO on phenotype, intracellular signaling pathways, Ca2+ influx and ADO production was analyzed in Breg and effector B cells (Beff) by FACS, luminescence and mass spectrometry. The blockage of the ADO receptor A2A was analyzed in a murine head and neck cancer model. RESULTS:ADO-producing Breg were found in tumor tissue and peripheral blood. ADO inhibited the intracellular Bruton's tyrosine kinase (BTK) and Ca2+ influx only in Beff. The inhibition of BTK by ibrutinib mimicked the effect of ADO, and ibrutinib reduced the production of ADO by downregulation of CD39 in vitro. The inhibition of ADO receptor A2A significantly reduced tumor mass and increased B cell infiltration, in vivo. CONCLUSION:Our data demonstrate the presence of a novel ADO-producing Breg population within the tumor microenvironment in mice and humans. A new model is proposed on how ADO-producing Breg can influence the function of Beff cells in healthy donors and cancer patients. Thus, the modulation of the ADO pathway in B cells may serve as a therapeutic approach for cancer patients.

SUBMITTER: Jeske SS

PROVIDER: S-EPMC7303082 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Adenosine-producing regulatory B cells in head and neck cancer.

Jeske Sandra S SS Brand Matthias M Ziebart Andreas A Laban Simon S Doescher Johannes J Greve Jens J Jackson Edwin K EK Hoffmann Thomas K TK Brunner Cornelia C Schuler Patrick J PJ

Cancer immunology, immunotherapy : CII 20200307 7

<h4>Background</h4>Multiple mechanisms of immunosuppression have been identified in the tumor microenvironment including regulatory B cells (B<sub>reg</sub>). Recently, we have shown that B<sub>reg</sub> suppress T cell function by production of adenosine (ADO). However, the autocrine effect of ADO on B cells and the role of B<sub>reg</sub> in head and neck cancer remains unclear.<h4>Methods</h4>Blood (n = 42) and tumor tissue (n = 39) of head and neck cancer patients and healthy donors (n = 60) ...[more]

PMID: 32146518

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Project description: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.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.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.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.

Project description:BackgroundRadioresistance represents a major problem in the treatment of head and neck cancer (HNC) patients. To improve response, understanding tumor microenvironmental factors that contribute to radiation resistance is important. Regulatory T cells (Tregs) are enriched in numerous cancers and can dampen the response to radiation by creating an immune-inhibitory microenvironment. The purpose of this study was to investigate mechanisms of Treg modulation by radiation in HNC.MethodsWe utilized an orthotopic mouse model of HNC. Anti-CD25 was used for Treg depletion. Image-guided radiation was delivered to a dose of 10 Gy. Flow cytometry was used to analyze abundance and function of intratumoral immune cells. Enzyme-linked immunosorbent assay was performed to assess secreted factors. For immune-modulating therapies, anti-PD-L1, anti-CTLA-4, and STAT3 antisense oligonucleotide (ASO) were used. All statistical tests were two-sided.ResultsTreatment with anti-CD25 and radiation led to tumor eradication (57.1%, n = 4 of 7 mice), enhanced T-cell cytotoxicity compared with RT alone (CD4 effector T cells [Teff]: RT group mean = 5.37 [ 0.58] vs RT + αCD25 group mean =10.71 [0.67], P = .005; CD8 Teff: RT group mean = 9.98 [0.81] vs RT + αCD25 group mean =16.88 [2.49], P = .01) and induced tumor antigen-specific memory response (100.0%, n = 4 mice). In contrast, radiation alone or when combined with anti-CTLA4 did not lead to durable tumor control (0.0%, n = 7 mice). STAT3 inhibition in combination with radiation, but not as a single agent, improved tumor growth delay, decreased Tregs, myeloid-derived suppressor cells, and M2 macrophages and enhanced effector T cells and M1 macrophages. Experiments in nude mice inhibited the benefit of STAT3 ASO and radiation.ConclusionWe propose that STAT3 inhibition is a viable and potent therapeutic target against Tregs. Our data support the design of clinical trials integrating STAT3 ASO in the standard of care for cancer patients receiving radiation.

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Adenosine-producing regulatory B cells in head and neck cancer.

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Adenosine-producing regulatory B cells in head and neck cancer.

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