Lung cancer-derived galectin-1 contributes to cancer associated fibroblast-mediated cancer progression and immune suppression through TDO2/kynurenine axis

Abstract

Communication between cancer cells and their microenvironment plays an important role in cancer development, but the precise mechanisms by which cancer-associated fibroblasts (CAF) impact anti-cancer immunity and cancer progression in lung cancer are poorly understood. Here, we report that lung fibroblasts when activated by lung cancer cells produce tryptophan metabolite kynurenine (Kyn) that inhibits dendritic cells' differentiation and induces cancer growth as well as migration. We identified TDO2 (tryptophan 2,3-dioxygenase) as the main enzyme expressed in fibroblasts capable of tryptophan metabolism. Mechanistically, condition medium of CAF or exogenous kynurenine stimulated AKT, with no lysine 1 (WNK1) and cAMP response element-bindingprotein (CREB) phosphorylation in lung cancer cells. Inhibition of the AKT/CREB pathway prevents cancer proliferation, while inhibition of the AKT/ WNK1 reverted epithelial-to-mesenchymal transition and cancer migration induced by kynurenine. Moreover, we also demonstrate that lung cancer-derived galectin-1 contributes to the upregulation of TDO2 in CAF through an AKT-dependent pathway. Immunohistochemical analysis of lung cancer surgical specimens revealed increased TDO2 expression in the fibroblasts adjacent to the cancer. Furthermore, in vivo studies showed that administration of TDO2 inhibitor significantly improves DCs function and T cell response, and decreases tumor metastasis in mice. Taken together, our data identify the feedback loop, consisting of cancer-derived galectin-1 and CAF-producing kynurenine, that sustains lung cancer progression. These findings suggest that targeting this pathway may be a promising therapeutic strategy.

Indoleamine 2,3‐dioxygenase 2 depletion suppresses tumor growth in a mouse model of Lewis lung carcinoma

“…In the present study, we showed that Ido2 deletion enhanced CD8 + cell invasion in the tumor microenvironment, and inhibited tumor growth in an LLC mouse model. This resulted from increases in tryptophan and decreases in kynurenine levels in the tumor microenvironment, which confirmed the results of previous reports, although the enzyme activity of Ido2 is much lower than that of Ido1. From these results the change in tryptophan metabolism caused by not only Ido1 and Tdo2, but also Ido2, was important in the induction of immune tolerance in tumors.…”

“…29 In addition, the treatment with a Tdo2 inhibitor improves dendritic cell function and T cell response significantly, leading to decreased tumor metastasis in mice. 30 F I G U R E 3 Levels of infiltrating immune cells at tumor sites in WT and indoleamine 2,…”

Metabolic Instruction of Immunity

“…For example, tumor cells manipulate surrounding adipocytes to increase lipolysis to whet their appetite for fatty acids (Nieman et al, 2011). Cancer associated fibroblasts degrade tryptophan that not only starves immune cells in the local environment of an essential amino acid, but also leads to the production of the immunosuppressive metabolite kynurenine (Hsu et al, 2016). Moreover, glucose is a critical substrate for the antitumor functions of effector T cells and M1 macrophages, which both require engagement of aerobic glycolysis for their activation and full effector functions (Buck et al, 2015; O’Neill and Pearce, 2016).…”

Crosstalk between cancer‐associated fibroblasts and immune cells in cancer

“…Cancer‐associated fibroblasts can also promote the invasion and metastasis of tumour cells. Cancer‐associated fibroblasts produce the tryptophan metabolite kynurenine and were shown to inhibit the differentiation of DCs and promote tumour cell growth and migration in lung cancer . Galectin‐1 upregulated tryptophan 2,3‐dioxygenase (TDO2) expression in CAFs.…”

“…Cancer-associated fibroblasts produce the tryptophan metabolite kynurenine and were shown to inhibit the differentiation of DCs and promote tumour cell growth and migration in lung cancer. 9 Galectin-1 upregulated tryptophan 2,3-dioxygenase (TDO2) expression in CAFs. The inhibition of TDO2 decreased tumour metastasis by promoting the T cell response in vivo.…”