CD4 + regulatory T (T reg ) cells accumulate in the tumor microenvironment (TME) and suppress the immune system. Whether and how metabolite availability in the TME influences T reg cell differentiation is not understood. Here, we measured 630 metabolites in the TME and found that serine and palmitic acid, substrates required for the synthesis of sphingolipids, were enriched. A serine-free diet or a deficiency in Sptlc2, the rate-limiting enzyme catalyzing sphingolipid synthesis, suppressed T reg cell accumulation and inhibited tumor growth. Sphinganine, an intermediate metabolite in sphingolipid synthesis, physically interacted with the transcription factor c-Fos. Sphinganine c-Fos interactions enhanced the genome-wide recruitment of c-Fos to regions near the transcription start sites of target genes including Pdcd1 (encoding PD-1), which promoted Pdcd1 transcription and increased inducible T reg cell differentiation in vitro in a PD-1–dependent manner. Thus, Sptlc2-mediated sphingolipid synthesis translates the extracellular information of metabolite availability into nuclear signals for T reg cell differentiation and limits antitumor immunity.

中文翻译：

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肿瘤中丝氨酸富集通过二氢鞘氨醇介导的 c-Fos 调节促进调节性 T 细胞积累

CD4+监管 T (T注册）细胞在肿瘤微环境（TME）中积聚并抑制免疫系统。 TME 中代谢物的可用性是否以及如何影响 T注册细胞分化尚不清楚。在这里，我们测量了 TME 中的 630 种代谢物，发现合成鞘脂所需的底物丝氨酸和棕榈酸被富集。无丝氨酸饮食或 Sptlc2（催化鞘脂合成的限速酶）缺陷会抑制 T注册细胞聚集并抑制肿瘤生长。二氢鞘氨醇是鞘脂合成的中间代谢物，与转录因子 c-Fos 发生物理相互作用。二氢鞘氨醇 c-Fos 相互作用增强了 c-Fos 在全基因组范围内招募到靶基因转录起始位点附近的区域，包括PDCD1（编码PD-1），这促进了PDCD1转录和增加诱导性 T注册体外细胞分化以 PD-1 依赖性方式进行。因此，Sptlc2介导的鞘脂合成将代谢物可用性的细胞外信息转化为T细胞的核信号。注册细胞分化并限制抗肿瘤免疫。