1. Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma.
- Author
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De Leo, Alessandra, Ugolini, Alessio, Yu, Xiaoqing, Scirocchi, Fabio, Scocozza, Delia, Peixoto, Barbara, Pace, Angelica, D'Angelo, Luca, Liu, James K.C., Etame, Arnold B., Rughetti, Aurelia, Nuti, Marianna, Santoro, Antonio, Vogelbaum, Michael A., Conejo-Garcia, Jose R., Rodriguez, Paulo C., and Veglia, Filippo
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MACROPHAGES , *GLIOBLASTOMA multiforme , *T cells , *MYELOID cells , *GLUCOSE metabolism - 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. [Display omitted] • Glycolytic MDMs are major contributors to the immunosuppression associated with TAMs • Intracellular lactate regulates IL-10 expression in MDMs via histone lactylation • PERK supports glucose metabolism in MDMs and regulates GLUT1 expression through ATF4 • PERK targeting blocks GBM progression in combination with immunotherapy There are no effective approaches to overcome the immunosuppressive activity of tumor-associated macrophages (TAMs). De Leo et al. report that monocyte-derived macrophages (MDMs), but not microglia (MGs), are major contributors to the immunosuppression associated with TAMs in glioblastoma and demonstrate that PERK-perturbed glucose metabolism drives MDM immunosuppressive programs via histone lactylation. Targeting of PERK-driven histone lactylation boosts the effect of immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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