Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada.
Trev and Joyce Deeley Research Centre, BC Cancer, Victoria, BC, Canada.
Sci Adv. 2021 Jan 20;7(4). doi: 10.1126/sciadv.abe1174. Print 2021 Jan.
Immune regulatory metabolites are key features of the tumor microenvironment (TME), yet with a few exceptions, their identities remain largely unknown. Here, we profiled tumor and T cells from tumor and ascites of patients with high-grade serous carcinoma (HGSC) to uncover the metabolomes of these distinct TME compartments. Cells within the ascites and tumor had pervasive metabolite differences, with a notable enrichment in 1-methylnicotinamide (MNA) in T cells infiltrating the tumor compared with ascites. Despite the elevated levels of MNA in T cells, the expression of nicotinamide -methyltransferase, the enzyme that catalyzes the transfer of a methyl group from -adenosylmethionine to nicotinamide, was restricted to fibroblasts and tumor cells. Functionally, MNA induces T cells to secrete the tumor-promoting cytokine tumor necrosis factor alpha. Thus, TME-derived MNA contributes to the immune modulation of T cells and represents a potential immunotherapy target to treat human cancer.
免疫调节代谢物是肿瘤微环境（TME）的关键特征，但除了少数例外，它们的身份在很大程度上仍然未知。在这里，我们对来自高级别浆液性卵巢癌（HGSC）患者的肿瘤和腹水的肿瘤和 T 细胞进行了分析，以揭示这些不同 TME 隔室的代谢组。腹水中和肿瘤内的细胞存在广泛的代谢物差异，与腹水中的 T 细胞浸润肿瘤相比，MNA（1-甲基烟酰胺）的水平明显升高。尽管 T 细胞中的 MNA 水平升高，但催化 - 腺苷甲硫氨酸向烟酰胺转移甲基的酶——烟酰胺 -N- 甲基转移酶的表达仅限于成纤维细胞和肿瘤细胞。功能上，MNA 诱导 T 细胞分泌促进肿瘤的细胞因子肿瘤坏死因子-α。因此，TME 衍生的 MNA 有助于 T 细胞的免疫调节，代表了一种治疗人类癌症的潜在免疫治疗靶标。
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