Indoleamine 2, 3-Dioxygenase Promotes Aryl Hydrocarbon Receptor-Dependent Differentiation Of Regulatory B Cells in Lung Cancer

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.

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“…With regard to tryptophan metabolism in tumors, IDO also mediates immune suppressive effects of MDSCs in breast cancer and lung cancer [ 290 , 291 ], and the upregulation of IDO in MDSCs depends on STAT3 phosphorylation [ 290 ]. Moreover, IDO associated with MDSCs also plays an important role in inducing the differentiation of Treg or Breg cells, which suppress anti-tumor immunity [ 292 , 293 ]. Inhibiting glutamine metabolism also blocks expression of IDO in MDSCs and tumor cell growth [ 294 ].…”

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“…Other data indicate that AhR activation by TCDD can induce regulatory functions in B-cells, without shifting these cells to a classical Breg phenotype [169]. This is evident in lung cancer where myeloid-derived suppressor cells' (MDSCs) induction of IDO leads to kynurenine that activates the AhR to induce Breg and immune suppression [170]. In long-lived plasma cells, the kynurenine activation of the AhR is essential to their longevity and function [171].…”

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“…AhR signaling also disturbed the differentiation of human natural killer (NK) cells [ 35 ] and mouse dendritic cells (DC) [ 36 ]. Interestingly, Tousif et al [ 37 ] demonstrated that AhR signaling promoted the differentiation of B cells into the regulatory B (Breg) cells in a mouse model of lung cancer. In addition, there is convincing evidence that an activation of AhR signaling induced the differentiation of mouse T cells into regulatory T (Treg) cells [ 38 , 39 ] (Fig.…”

“…They also reported that the activation of AhR signaling suppressed hepatic steatosis occurring when mice were fed a high fat diet. Moreover, the activation of AhR signaling stimulates the differentiation of immunosuppressive phenotypes of many immune cells, i.e., (i) induction of myeloid-derived suppressor cells (MDSC) [ 151 ], (ii) Tregs [ 38 ], (iii) Bregs [ 37 ], (iv) tolerogenic dendritic cells (tolDC) [ 152 ], and (v) M2 macrophages (Mreg) [ 153 ]. For instance, AhR signaling stimulated the expression of Forkhead box 3 (FoxP3) protein, a master regulator of Tregs [ 38 ] (Fig.…”