Abstract 1590: The oncometabolite D2HG reprograms macrophages to drive immunosuppression in IDH1-mutant cholangiocarcinoma

作者：Sara E. Young, Emma Kartalia, Johnathan DeBetta, James Leatherman, Kayla J. Bendinelli, Tamara Y. Lopez-Vidal, Edwin Y. He, Mark Yarchoan, Daniel J. Zabransky · 发表于：Cancer Research · 年份：2026 · DOI：10.1158/1538-7445.am2026-1590 · 研究领域：Cholangiocarcinoma and Gallbladder Cancer Studies、Liver Diseases and Immunity、Immune cells in cancer

Abstract Background: Intrahepatic cholangiocarcinoma (CCA) is an aggressive primary liver cancer, with ∼20% of cases driven by mutations in isocitrate dehydrogenase 1 (mIDH1). Compared with IDH1 wild-type tumors, mIDH1 CCA exhibits an immunosuppressive microenvironment enriched for M2-like macrophages and may derive reduced benefit from immune checkpoint therapy than the general CCA population, suggesting tumor-immune interactions contribute to therapeutic resistance. mIDH1 tumors secrete the oncometabolite D2HG, but its effects on macrophages within the tumor microenvironment (TME) remain incompletely understood. Methods: We exposed THP-1 monocytes, a human myeloid leukemia cell line commonly used to model macrophage differentiation, and PBMC-derived macrophages to D2HG. Flow cytometry, RT-qPCR, and Luminex were used to assess expression of immunosuppressive markers (CD206, CD163, IL-10) and cytokine secretion (IL-10, IL-4, IL-13). Lipid uptake and accumulation was quantified by BODIPY staining, and CD36 expression was measured by flow cytometry and RT-qPCR. Seahorse metabolic assays and fatty acid oxidation analyses evaluated metabolic activity, while phagocytosis assays with live-cell imaging assessed macrophage function. Results: Exposure to pathologically relevant levels of D2HG that mirror those in the mIDH1 TME led THP-1 and PBMC-derived macrophages to upregulate immunosuppressive markers including CD206, CD163, and IL-10, while also increasing secretion of IL-10, IL-4...