Serine enrichment in tumors promotes regulatory T cell accumulation through sphinganine-mediated regulation of c-Fos
Sicong Ma, Roger Sandhoff, Xiu Luo, Fuwei Shang, Qiaozhen Shi, Zhaolong Li, Jingxia Wu, Yanan Ming, Frank Schwarz, Alaa Madi, Nina Weisshaar, Alessa Mieg, Marvin Hering, Ferdinand Zettl, Xin Yan, Kerstin Möhr, Nora ten Bosch, Zhe Li, Gernot Poschet, Hans‐Reimer Rodewald, F. Nina Papavasiliou, Xi Wang, Pu Gao, Guoliang Cui
Abstract
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.