Head and neck carcinoma – How adenosine influences B cells

Introduction:

Activated CD73+ regulatory B cells (Breg) acquire the capability to downregulate the proliferation of autologous CD4+ TH cells via immunosuppressive adenosine (ADO). Exogenous ADO is present in high concentrations in solid tumors like head and neck tumors. Immune suppression in the tumor microenvironment may cause increased tumor growth and metastasis. However, intracellular mechanisms in Breg upon ADO-binding are not completely understood.

Methods:

Peripheral blood mononuclear cells and tumor infiltrating lymphocytes were isolated from head and neck cancer patients and healthy volunteers. Phenotypes, activity of intracellular proteins as well as Calcium influx into the cell induced by B cell receptor- (BCR) stimulation were determined. The influence of exogenous ADO on intracellular signaling pathways was determined in healthy volunteers. Additionally, in activated B cells the production of ADO was analyzed under treatment with BCR-inhibitors.

Results:

On the basis of CD73-expression we were able to identify CD73- B cells as well as CD73+ B cells (Breg) in patient's blood as well as in tumor tissue. Exogenous ADO was shown to inhibit the BCR-mediated signaling pathways and the Ca2+-influx of CD73- B cells but not of CD73+ Breg. Treatment with BCR-pathway specific inhibitors mimics this effect and potentiates the effect of ADO. Additionally, ADO-production of B cells can be inhibited by pathway specific inhibitors.

Conclusion:

The data show that ADO-producing CD73+ B cells (Breg) inhibit the function of CD73- B cells. Intracellular key regulators of ADO-production in Breg may serve as therapeutic targets in the treatment of cancer patients, especially in combination with established immunotherapeutic approaches.

Publication History

Publication Date:
18 April 2018 (online)