Abstract
Immunosuppressive macrophages restrict anti-cancer immunity in glioblastoma (GBM). Here, we studied the contribution of microglia (MGs) and monocyte-derived macrophages (MDMs) to immunosuppression and mechanisms underlying their regulatory function. MDMs outnumbered MGs at late tumor stages and suppressed T cell activity. Molecular and functional analysis identified a population of glycolytic MDM expressing GLUT1 with potent immunosuppressive activity. GBM-derived factors promoted high glycolysis, lactate, and interleukin-10 (IL-10) production in MDMs. Inhibition of glycolysis or lactate production in MDMs impaired IL-10 expression and T cell suppression. Mechanistically, intracellular lactate-driven histone lactylation promoted IL-10 expression, which was required to suppress T cell activity. GLUT1 expression on MDMs was induced downstream of tumor-derived factors that activated the PERK-ATF4 axis. PERK deletion in MDM abrogated histone lactylation, led to the accumulation of intratumoral T cells and tumor growth delay, and, in combination with immunotherapy, blocked GBM progression. Thus, PERK-driven glucose metabolism promotes MDM immunosuppressive activity via histone lactylation.
免疫抑制巨噬细胞限制了胶质母细胞瘤（GBM）的抗癌免疫。在这项研究中，我们研究了小胶质细胞（MGs）和单核细胞衍生巨噬细胞（MDMs）对免疫抑制的贡献及其调节功能的机制。在肿瘤晚期，MDMs的数量超过了MGs，并抑制了T细胞的活性。分子和功能分析确定了表达GLUT1的糖酵解MDM 群体，它们具有强大的免疫抑制活性。源自GBM的因子促进了MDM的高糖酵解、乳酸和白细胞介素-10（IL-10）的产生。抑制MDMs中的糖酵解或乳酸生成会损害IL-10的表达和T细胞抑制。从机制上讲，细胞内乳酸驱动的组蛋白乳酸化促进了IL-10的表达，而IL-10的表达是抑制T细胞活性所必需的。MDMs上的GLUT1表达是由激活PERK-ATF4轴的肿瘤衍生因子诱导的。在 MDM 中敲除PERK可抑制组蛋白乳酸化，导致瘤内T细胞聚集和肿瘤生长延迟，与免疫疗法相结合可阻止GBM进展。因此，PERK驱动的葡萄糖代谢通过组蛋白乳酸化促进MDM的免疫抑制活性。
De Leo A, Ugolini A, Yu X, Scirocchi F, Scocozza D, Peixoto B, Pace A, D'Angelo L, Liu JKC, Etame AB, Rughetti A, Nuti M, Santoro A, Vogelbaum MA, Conejo-Garcia JR, Rodriguez PC, Veglia F. Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma. Immunity. 2024 May 14;57(5):1105-1123.e8. doi: 10.1016/j.immuni.2024.04.006. Epub 2024 May 3. PMID: 38703775; PMCID: PMC11114377.
