Abstract
Regulatory B cells (Breg) are IL-10 producing subsets of B cells that contribute to immunosuppression in the tumor microenvironment (TME). Breg are elevated in patients with lung cancer; however, the mechanisms underlying Breg development and their function in lung cancer have not been adequately elucidated. Herein, we report a novel role for Indoleamine 2, 3- dioxygenase (IDO), a metabolic enzyme that degrades tryptophan (Trp) and the Trp metabolite L-kynurenine (L-Kyn) in the regulation of Breg differentiation in the lung TME. Using a syngeneic mouse model of lung cancer, we report that Breg frequencies significantly increased during tumor progression in the lung TME and secondary lymphoid organs, while Breg were reduced in tumor-bearing IDO deficient mice (IDO-/-). Trp metabolite L-Kyn promoted Breg differentiation in-vitro in an aryl hydrocarbon receptor (AhR), toll-like receptor-4-myeloid differentiation primary response 88, (TLR4-MyD88) dependent manner. Importantly, using mouse models with conditional deletion of IDO in myeloid-lineage cells, we identified a significant role for immunosuppressive myeloid-derived suppressor cell (MDSC)-associated IDO in modulating in-vivo and ex-vivo differentiation of Breg. Our studies thus identify Trp metabolism as a therapeutic target to modulate regulatory B cell function during lung cancer progression.
Highlights
Lung Cancer is the leading cause of cancer-associated morbidity and mortality among men and women, claiming ~1.3 million deaths annually worldwide [1,2,3]
We demonstrate that splenic Breg frequency increases with the progression of lung tumor growth in a syngeneic model of lung cancer
Data shown here are pooled from four independent experiments with 3 technical replicates in each condition. (B, D, F) Lower panel- L-Kyn promoted Breg precursors (CD19+CD1dhiCD5+) in B cells of Toll-like receptor (TLR)-4-/- toll-like receptor-2 (TLR-2)-/- and TLR-2, 4-/- following stimulation with LPS+L-Kyn
Summary
Lung Cancer is the leading cause of cancer-associated morbidity and mortality among men and women, claiming ~1.3 million deaths annually worldwide [1,2,3]. The tumor microenvironment (TME) plays a dynamic role in regulating immune responses during the progression of lung cancer [4, 5]. Tumor promoting myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg) are known contributors of immunosuppression in the TME [9, 10]. Recent studies have emphasized a regulatory function for subsets of B cells called regulatory B cells (Breg) in inhibiting anti-tumor immune responses [11,12,13,14,15,16]. IL-10 producing B cell subsets (Breg) that are CD1d high were first identified by Mizuguchi et al in 2002 in the study of chronic intestinal inflammation [20]. Previous studies have reported that Breg suppress anti-tumor T cell responses through induction of Treg [10]
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