Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
Division of Pharmacology, Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.
Nat Commun. 2024 Nov 1;15(1):9464. doi: 10.1038/s41467-024-53706-3.
While prostaglandin E (PGE) is produced in human tumor microenvironment (TME), its role therein remains poorly understood. Here, we examine this issue by comparative single-cell RNA sequencing of immune cells infiltrating human cancers and syngeneic tumors in female mice. PGE receptors EP4 and EP2 are expressed in lymphocytes and myeloid cells, and their expression is associated with the downregulation of oxidative phosphorylation (OXPHOS) and MYC targets, glycolysis and ribosomal proteins (RPs). Mechanistically, CD8 T cells express EP4 and EP2 upon TCR activation, and PGE blocks IL-2-STAT5 signaling by downregulating Il2ra, which downregulates c-Myc and PGC-1 to decrease OXPHOS, glycolysis, and RPs, impairing migration, expansion, survival, and antitumor activity. Similarly, EP4 and EP2 are induced upon macrophage activation, and PGE downregulates c-Myc and OXPHOS in M1-like macrophages. These results suggest that PGE-EP4/EP2 signaling impairs both adaptive and innate immunity in TME by hampering bioenergetics and ribosome biogenesis of tumor-infiltrating immune cells.
虽然前列腺素 E（PGE）在人类肿瘤微环境（TME）中产生，但它在其中的作用仍不清楚。在这里，我们通过对女性小鼠中同种异体肿瘤和人类癌症浸润免疫细胞的比较单细胞 RNA 测序来研究这个问题。PGE 受体 EP4 和 EP2 在淋巴细胞和髓样细胞中表达，其表达与氧化磷酸化（OXPHOS）和 MYC 靶标的下调、糖酵解和核糖体蛋白（RPs）有关。从机制上讲，CD8 T 细胞在 TCR 激活时表达 EP4 和 EP2，PGE 通过下调 Il2ra 来阻断 IL-2-STAT5 信号，从而下调 c-Myc 和 PGC-1 以降低 OXPHOS、糖酵解和 RPs，从而损害迁移、扩张、存活和抗肿瘤活性。同样，巨噬细胞激活时也会诱导 EP4 和 EP2，PGE 下调 M1 样巨噬细胞中的 c-Myc 和 OXPHOS。这些结果表明，PGE-EP4/EP2 信号通过阻碍肿瘤浸润免疫细胞的生物能量和核糖体生物发生来损害 TME 中的适应性和固有免疫。
