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Targeting LYPLAL1-mediated cGAS depalmitoylation enhances the response to anti-tumor immunotherapy

ABSTRACT: Targeting LYPLAL1-mediated cGAS depalmitoylation enhances the response to anti-tumor immunotherapy

PROVIDER: PRJNA1010803 | ENA |

REPOSITORIES: ENA

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Targeting LYPLAL1-mediated cGAS depalmitoylation enhances the response to anti-tumor immunotherapy

Project description:Cyclic GMP-AMP synthase (cGAS) binds pathogenic and other cytoplasmic double-stranded DNA (dsDNA) to catalyze the synthesis of cyclic GMP-AMP (cGAMP), which serves as the secondary messenger to activate the STING pathway and innate immune responses. Emerging evidence suggests that activation of the cGAS pathway is crucial for anti-tumor immunity, however, no effective intervention method targeting cGAS is currently available. Here we report that cGAS is palmitoylated by ZDHHC9 at cysteines 404/405, which promotes the dimerization and activation of cGAS. We further identified that lysophospholipase-like 1 (LYPLAL1) depalmitoylates cGAS to compromise its normal function. As such, inhibition of LYPLAL1 significantly enhances cGAS-mediated innate immune response, elevates PD-L1 expression and enhances anti-tumor response to PD-1 blockade. Our results therefore reveal that targeting LYPLAL1-mediated cGAS depalmitoylation contributes to cGAS activation, providing a potential strategy to augment the efficacy of anti-tumor immunotherapy.

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Targeting PRMT3 Impairs Methylation and Oligomerization of HSP60 to Boost Anti-Tumor Immunity by Activating cGAS/STING Signaling

Project description:Hepatocellular carcinoma (HCC) is a highly lethal cancer for which current available treatment options have limited efficacy. Immunotherapy has emerged as a promising therapeutic option for HCC, yet resistance to immunotherapy is a major challenge. Here, we uncover protein arginine methyltransferase 3 (PRMT3) as a novel driver of immunotherapy resistance in HCC. We show that PRMT3 expression is induced by activated T cells in response to immune checkpoint blockade (ICB) via an interferon-gamma (IFN)STAT1 signaling pathway, and that high PRMT3 expression inversely correlates with tumor-infiltrating CD8+ T cells and predicts poor response to ICB in HCC patients. We demonstrate that genetic depletion and pharmacological inhibition of PRMT3 induce a profound influx of T cells into tumors and activate anti-tumor immunity to suppress HCC progression. Mechanistically, we demonstrate that PRMT3 methylates HSP60, a mitochondrial chaperone protein, at R446, and that this novel post-translational modification is required for HSP60 oligomerization and maintaining mitochondrial homeostasis. We reveal that targeting PRMT3-dependent HSP60-R446 methylation boosts anti-tumor immunity by disrupting mitochondrial function, increasing mitochondrial DNA (mtDNA) leakage, and activating the cGAS/STING pathway, a key innate immune sensor of cytosolic DNA. Importantly, we provide genetic and pharmacologic evidence that targeting PRMT3 enhances anti-PD1 efficacy and anti-tumor immunity in HCC mouse models. Our study identifies PRMT3 as a potential biomarker and therapeutic target to overcome immunotherapy resistance in HCC.

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Targeting TREM2 on tumor associated macrophages enhances efficacious immunotherapy

Project description:Targeting TREM2 on tumor associated macrophages enhances efficacious immunotherapy

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ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage/cGAS-STING activation

Project description:ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage/cGAS-STING activation

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ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage/cGAS-STING activation [B16 vivo]

Project description:ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage/cGAS-STING activation [B16 vivo]

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Targeting Arginine Methylation Suppresses Cancer Stem Cell Maintenance and Elicits cGAS-mediated anti-Cancer Immunity

Project description:Current anti-cancer therapies cannot eliminate all the cancer cells, which hijack normal arginine methylation as a means to promote their own maintenance via unknown mechanisms. Herein, we show that targeting protein arginine methyltransferase 9 (PRMT9), whose activities are elevated in leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML), eliminates disease via cancer-intrinsic mechanisms and cancer-extrinsic Type-I Interferon (IFN-I)-associated immunity. PRMT9 ablation in AML cells decreased arginine methylation of regulators of RNA translation and the DNA damage response, suppressing cell survival. Notably, PRMT9 inhibition promoted DNA damage and activated cGAS, which underlies the IFN-I response. Genetically activating cGAS in AML cells blocked leukemogenesis. We also report synergy of a PRMT9 inhibitor with anti-PD1 in eradicating PRMT9-proficient cancers, including AML and lymphoma. We conclude that PRMT9 governs LSCs survival and immune evasion, and that combining a PRMT9 inhibitor with an immune checkpoint inhibitor represents a novel anti-cancer strategy.

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Targeting Arginine Methylation Suppresses Cancer Stem Cell Maintenance and Elicits cGAS-mediated anti-Cancer Immunity

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Targeting Arginine Methylation Suppresses Cancer Stem Cell Maintenance and Elicits cGAS-mediated anti-Cancer Immunity II

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