title: 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.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Hsu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jen-Yu
authors.initials: JY
authors.lastname: Hung
authors.affiliation: Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Shin-Yi
authors.initials: SY
authors.lastname: Chiang
authors.affiliation: Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Shu-Fang
authors.initials: SF
authors.lastname: Jian
authors.affiliation: Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Cheng-Ying
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yi-Shiuan
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Ying-Ming
authors.initials: YM
authors.lastname: Tsai
authors.affiliation: Division of Chest Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Shah-Hwa
authors.initials: SH
authors.lastname: Chou
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Ming-Ju
authors.initials: MJ
authors.lastname: Tsai
authors.affiliation: Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Kuo
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000072645:Cancer-Associated Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D018450:Disease Progression; D037483:Galectin 1 / Q000276:immunology / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D007737:Kynurenine / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D015398:Signal Transduction; D014366:Tryptophan Oxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D037483:Galectin 1; D007737:Kynurenine; D014366:Tryptophan Oxygenase
keywords: cancer-associated fibroblasts; galectin-1; kynurenine; lung cancer