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

Autor:	De Leo A; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA., Ugolini A; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA; Department of Experimental Medicine 'Sapienza' University of Rome, Rome, Italy., Yu X; Department of Biostatistics and Bioinformatic, H. Lee Moffitt Cancer Center, Tampa, FL, USA., Scirocchi F; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Department of Experimental Medicine 'Sapienza' University of Rome, Rome, Italy., Scocozza D; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, USA., Peixoto B; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA., Pace A; Department of Experimental Medicine 'Sapienza' University of Rome, Rome, Italy., D'Angelo L; Department of Human Neurosciences, Neurosurgery Division, 'Sapienza' University, AOU Policlinico Umberto I, Rome, Italy., Liu JKC; Department of Neuro-Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA., Etame AB; Department of Neuro-Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA., Rughetti A; Department of Experimental Medicine 'Sapienza' University of Rome, Rome, Italy., Nuti M; Department of Experimental Medicine 'Sapienza' University of Rome, Rome, Italy., Santoro A; Department of Human Neurosciences, Neurosurgery Division, 'Sapienza' University, AOU Policlinico Umberto I, Rome, Italy., Vogelbaum MA; Department of Neuro-Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA., Conejo-Garcia JR; Department of Integrative immunobiology, Duke School of Medicine, Durham, NC, USA., Rodriguez PC; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, USA., Veglia F; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Department of Neuro-Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA. Electronic address: fveglia@wistar.org.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2024 May 14; Vol. 57 (5), pp. 1105-1123.e8. Date of Electronic Publication: 2024 May 03.
DOI:	10.1016/j.immuni.2024.04.006
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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