Science Immunology, 19 April, 2024, DOI：https://doi.org/10.1126/sciimmunol.adg8817

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 Mohr, Nora Ten Bosch, Zhe Li, Gernot Poschet, Hans-Reimer Rodewald, Nina Papavasiliou, Xi Wang, Pu Gao, And 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.

Article link：https://www.science.org/doi/10.1126/sciimmunol.adg8817