03714177

December 21, 2021, 15:23

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T cells in pancreatic cancer stroma：tryptophan metabolism plays an important role in immunoregulation. Ting Yang1, Zhengyin Liao1, Biao Yang1,* 1, Department of Gastroenterology, West China hospital, Sichuan University, P.R.China To the editor, We have an interest in the recently published article by Goulart et al., (1) summarizing that the pancreatic cancer (PC) immune landscape, T cell interactions and immune dysfunction, T cell phenotype and functions, T cell exhaustion, and immunotherapy in PC. In this review, Goulart et al., summarized that the immune cells, including CD8+T, NK, Th17, and Treg cells are regulated by different cytokine factors. However, several studies have shown that immune system are highly regulated by tryptophan metabolism. As we all known, indoleamine 2,3-dioxygenase 1 (IDO1), as an intracellular enzyme which participates in the metabolism of the essential amino acid tryptophan (TRP) in the kynurenine (KYN) pathway, is an independent prognostic marker for PC. There are numerous evidences for tryptophan metabolism served as an immunomodulatory factor. First, IDO1 overexpression inhibits the maturation of CD11c and DCs, and T-cell proliferation in liver and spleen (2). Second, highly expression of KYN induces and activates aryl hydrocarbon receptor (AhR) results in upregulates PD-1 expression. Inhibition of Kyn-AhR) pathway can enhance antitumor adoptive T cell therapy efficacy, and reduce the rate of migration and invasion in both tumor-bearing mice and patients with cancer (3). In vivo experiments, inactivation of Kyn-AhR pathway showed ameliorate IDO1-mediated immunosuppression(4). In a clinical study, higly transcript of AhR were correlated with reduced CD8 T cell infiltration and worse outcomes in patients with PC(5). Third, The indction of IDO1 can lead to the loss of TH17/Treg balance in vivo. Similarly, the loss of TH17/Treg balance is mediated by the proximal tryptophan catabolite from IDO metabolism(6). In our study, we found that overexpression of IDO upregulates the CD8+ T cells and reduce NKT cells in both hepatic cancer and pancreatic carcinoma in mice. Hence, it’s essential to pay more attention to tryptophan metabolism in patients with PC, especially in those who were tolerant to immunotherapy. Reference 1. Goulart MR, Stasinos K, Fincham REA, Delvecchio FR, Kocher HM. T cells in pancreatic cancer stroma. World J Gastroenterol 2021; 27(46): 7956-7968. 2. Mo, Chan, et al. "Indoleamine 2, 3-dioxygenase 1 limits hepatic inflammatory cells recruitment and promotes bile duct ligation-induced liver fibrosis." Cell death & disease 12.1 (2021): 1-15. 3，Liu, Yuying, et al. "Tumor-repopulating cells induce PD-1 expression in CD8+ T cells by transferring kynurenine and AhR activation." Cancer cell 33.3 (2018): 480-494. 4，Liang, Heng, et al. "IDO1/TDO dual inhibitor RY103 targets Kyn-AhR pathway and exhibits preclinical efficacy on pancreatic cancer." Cancer Letters 522 (2021): 32-43. 5，Hezaveh, Kebria, et al. "Microbiome-Driven Tryptophan Metabolism Suppresses Immunity in the Pancreatic Tumor Microenvironment by Activation of the Aryl Hydrocarbon Receptor." 6，Favre, David, et al. "Tryptophan catabolism by indoleamine 2, 3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease." Science translational medicine 2.32 (2010): 32ra36-32ra36.

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