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Deregulated inflammation is a critical feature driving the progression of tumors harboring mutations in the liver kinase B1 (LKB1), yet the mechanisms linking LKB1 mutations to deregulated inflammation remain undefined. Here, we identify deregulated signaling by CREB-regulated transcription coactivator 2 (CRTC2) as an epigenetic driver of inflammatory potential downstream of LKB1 loss. We demonstrate that LKB1 mutations sensitize both transformed and non-transformed cells to diverse inflammatory stimuli, promoting heightened cytokine and chemokine production. LKB1 loss triggers elevated CRTC2-CREB signaling downstream of the salt-inducible kinases (SIKs), increasing inflammatory gene expression in LKB1-deficient cells. Mechanistically, CRTC2 cooperates with the histone acetyltransferases CBP/p300 to deposit histone acetylation marks associated with active transcription (i.e., H3K27ac) at inflammatory gene loci, promoting cytokine expression. Together, our data reveal a previously undefined anti-inflammatory program, regulated by LKB1 and reinforced through CRTC2-dependent histone modification signaling, that links metabolic and epigenetic states to cell-intrinsic inflammatory potential. [Display omitted] • Loss of LKB1 sensitizes cells to diverse inflammatory stimuli • LKB1 regulates inflammatory responses via CRTC2-CREB signaling • Loss of LKB1 promotes increased CRTC2-dependent H3K27ac at inflammatory gene loci • Increased histone acetylation boosts inflammatory potential in LKB1-deficient cells Deregulated inflammation is a critical feature driving the progression of tumors harboring mutations in liver kinase B1 (LKB1). Compton et al. identify a mechanism by which LKB1 epigenetically regulates cellular inflammatory potential through CRTC2-dependent histone acetylation at inflammatory gene loci. [ABSTRACT FROM AUTHOR]

Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)—including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)—as essential fuels supporting CD8+ T cell metabolism and effector function. βOHB directly increased CD8+ T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8+ Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8+ T cell function. Mechanistically, βOHB was a major substrate for acetyl-CoA production in CD8+ T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8+ T cell effector responses. [Display omitted] • Ketolysis regulates CD8+ T cell metabolism and effector responses in vivo • Exogenous ketone bodies enhance CD8+ T cell bioenergetics and cytokine production • The ketone body βOHB is preferred over glucose for synthesis of acetyl-CoA • βOHB-derived acetyl-CoA regulates histone acetylation at effector gene loci Environmental nutrient availability influences T cell function, yet the substrates that fuel T cell metabolism in vivo are poorly defined. Here, Luda and Longo et al. identify ketolysis (breakdown of ketone bodies) as a metabolic pathway required for optimal CD8+ T cell effector function in vivo. Ketone bodies, including βOHB, are physiologic fuels for T cells, preferred over glucose for acetyl-CoA synthesis, and regulate effector function through effects on histone acetylation. [ABSTRACT FROM AUTHOR]

How environmental nutrient availability impacts T cell metabolism and function remains poorly understood. Here, we report that the presence of physiologic carbon sources (PCSs) in cell culture medium broadly impacts glucose utilization by CD8 + T cells, independent of transcriptional changes in metabolic reprogramming. The presence of PCSs reduced glucose contribution to the TCA cycle and increased effector function of CD8 + T cells, with lactate directly fueling the TCA cycle. In fact, CD8 + T cells responding to Listeria infection preferentially consumed lactate over glucose as a TCA cycle substrate in vitro, with lactate enhancing T cell bioenergetic and biosynthetic capacity. Inhibiting lactate-dependent metabolism in CD8 + T cells by silencing lactate dehydrogenase A (Ldha) impaired both T cell metabolic homeostasis and proliferative expansion in vivo. Together, our data indicate that carbon source availability shapes T cell glucose metabolism and identifies lactate as a bioenergetic and biosynthetic fuel for CD8 + effector T cells., Competing Interests: Declaration of interests R.J.D. is a founder and consultant for Atavistik Biosciences and an advisor for Agios Pharmaceuticals, Nirogy Therapeutics, and Vida Ventures. R.G.J. is a scientific advisor for Agios Pharmaceuticals and Servier Pharmaceuticals and is a member of the Scientific Advisory Board of Immunomet Therapeutics., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cancer cells display metabolic plasticity to survive stresses in the tumor microenvironment. Cellular adaptation to energetic stress is coordinated in part by signaling through the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Here, we demonstrate that miRNA-mediated silencing of LKB1 confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides. Using both classic (phenformin) and newly developed (IM156) biguanides, we demonstrate that elevated miR-17∼92 expression in Myc + lymphoma cells promotes increased apoptosis to biguanide treatment in vitro and in vivo . This effect is driven by the miR-17 -dependent silencing of LKB1, which reduces AMPK activation in response to complex I inhibition. Mechanistically, biguanide treatment induces metabolic stress in Myc + lymphoma cells by inhibiting TCA cycle metabolism and mitochondrial respiration, exposing metabolic vulnerability. Finally, we demonstrate a direct correlation between miR-17∼92 expression and biguanide sensitivity in human cancer cells. Our results identify miR-17∼92 expression as a potential biomarker for biguanide sensitivity in malignancies., Competing Interests: R.G.J. and M.N.P. serve on the Scientific Advisory Board of ImmunoMet Therapeutics. M.S.R. is a consultant to ImmunoMet Therapeutics. S.Y. is an employee of ImmunoMet Therapeutics. R.G.J. and ImmunoMet Therapeutics hold a provisional patent for the use of IM156 for treatment of malignancy based on miR-17∼92, Myc, or LKB1 expression., (© 2020 The Author(s).)