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.

Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma / 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.; Veglia, Filippo. - In: IMMUNITY. - ISSN 1074-7613. - 57:(2024), pp. 1-9. [10.1016/j.immuni.2024.04.006]

Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma

Ugolini, Alessio
Primo
;
Scirocchi, Fabio;Pace, Angelica;Rughetti, Aurelia;Nuti, Marianna;Santoro, Antonio;
2024

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.
2024
ER stress; PERK; brain cancer; glioblastoma; glycolysis; histone lactylation; immunosuppression; metabolism; myeloid cells; tumor-associated macrophages
01 Pubblicazione su rivista::01a Articolo in rivista
Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma / 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.; Veglia, Filippo. - In: IMMUNITY. - ISSN 1074-7613. - 57:(2024), pp. 1-9. [10.1016/j.immuni.2024.04.006]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1709706
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