Metabolic Reprogramming via targeting the ACOD1/KEAP1/NRF2 axis promotes polarization and anti-tumor activity of human CAR-iMACs in solid tumors
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE216354 | GEO | 2023/08/03
REPOSITORIES: GEO
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Project description:Metabolic Reprogramming via targeting the ACOD1/KEAP1/NRF2 axis promotes polarization and anti-tumor activity of human CAR-iMACs in solid tumors
| PRJNA893200 | ENA
Project description:Chimeric antigen receptor (CAR)-T cell therapies have shown great success in treating hematologic malignancies. Nonetheless, their therapeutic effect on solid tumors remains to be improved. Recently, macrophages have attracted great attention, given their ability to infiltrate solid tumors, phagocytize tumor cells as well as their immunomodulatory capacities. The first generation of CD3ζ-based CAR-macrophages demonstrated that the CAR could stimulate macrophage phagocytosis in a tumor antigen-dependent way. Here, we genetically engineered induced pluripotent stem cell (iPSC)-derived macrophages (iMACs) with TLR4 intracellular TIR domain-containing CARs against EGFRvIII and GPC3, which yielded markedly enhanced antitumor effect in two different solid tumor models including glioblastoma, and hepatocellular carcinoma in which complete remission was achieved with CAR-iMACs alone or in combination with CD47 antibody. Moreover, the tandem CD3ζ-TIR-CAR, or the “second-generation” design of TIR-based dual signaling CAR, endowed iMACs with both target engulfment/efferocytosis capacity against antigen-expressing solid tumor cells, and potency of antigen-dependent M1 state polarization and M2 state resistance in an NF-κB dependent manner. We also illustrated a surprising mechanism of tumor cell elimination by CAR-induced efferocytosis against tumor cell apoptotic bodies. Taken together, we established the next generation CAR-iMACs equipped with orthogonal phagocytosis and polarization capacity for better antitumor functions in treating solid tumors.
2023-09-29 | GSE214140 | GEO
Project description:Inflammatory macrophages are key drivers of atherosclerosis that can induce rupture-prone vulnerable plaques. Skewing the plaque macrophage population towards a more protective phenotype and reducing the occurrence of clinical events is thought to be a promising method of treating atherosclerotic patients. In the current study, we investigate the immunomodulatory properties of itaconate, an immunometabolite derived from the TCA cycle intermediate cis-aconitate and synthesised by the enzyme Aconitate Decarboxylase 1 (ACOD1, also known as IRG1), in the context of atherosclerosis. Ldlr-/- atherogenic mice transplanted with Acod1-/- bone marrow displayed a more stable plaque phenotype with smaller necrotic cores and showed increased recruitment of monocytes to the vessel intima. Macrophages from Acod1-/- mice contained more lipids whilst also displaying reduced induction of apoptosis. Using multi-omics approaches, we identify a metabolic shift towards purine metabolism, in addition to an altered glycolytic flux towards production of glycerol for triglyceride synthesis. Overall, our data highlight the potential of therapeutically blocking ACOD1 with the aim of stabilizing atherosclerotic plaques.
| S-EPMC10848031 | biostudies-literature
Project description:The pro-inflammatory state of macrophages, underpinned by their metabolic condition, is essentially affecting their capacity of combating tumor cells. Here we find, via a pooled metabolic gene knockout CRISPR screen that KEAP1 and ACOD1 are strong regulators of the pro-inflammatory state in macrophages. We show that ACOD1 knockout macrophages, generated in our induced pluripotent stem cell-derived CAR-macrophage (CAR-iMAC) platform, are strongly and persistently polarized toward the pro-inflammatory state, which manifests in increased reactive oxygen species (ROS) production, more potent phagocytosis and enhanced cytotoxic functions against cancer cells in vitro. In ovarian or pancreatic cancer mouse models, ACOD1-depleted CAR-iMACs exhibit enhanced capacity in repressing tumors, leading to increased survival. In addition, combining ACOD1-depleted CAR-iMACs with immune checkpoint inhibitors (ICI), such as anti-CD47 or anti-PD1 antibodies, result in even stronger tumor suppressing effect. Mechanistically, the depletion of ACOD1 reduces levels of the immuno-metabolite itaconate, allowing KEAP1 to prevent NRF2 from entering the nucleus to activate an anti-inflammatory program. This study thus lays down the proof of principle for targeting ACOD1 in myeloid cells for cancer immunotherapy and introduces metabolically engineered human iPSC-derived CAR-iMACs cells with enhanced polarization and anti-tumor functions in adoptive cell transfer therapies.
| S-EPMC10507032 | biostudies-literature
Project description:Oxidative and electrophilic changes in cells are mainly coordinated by the KEAP1/NRF2 (Kelch-like erythroid-derived cap-n-collar homology- (ECH-) associated protein-1/nuclear factor (erythroid-derived 2)-like 2) axis. The physical interaction between these two proteins promotes the expression of several antioxidant defense genes in response to exogenous and endogenous insults. Recent studies demonstrated that KEAP1/NRF2 axis dysfunction is also strongly related to tumor progression and chemo- and radiotherapy resistance of cancer cells. In solid tumors, the KEAP1/NRF2 system is constitutively activated by the loss of KEAP1 or gain of NFE2L2 functions that leads to its nuclear accumulation and enhances the transcription of many cytoprotective genes. In addition to point mutations, epigenetic abnormalities, as aberrant promoter methylation, and microRNA (miRNA) and long noncoding RNA (lncRNA) deregulation were reported as emerging mechanisms of KEAP1/NRF2 axis modulation. This review will summarize the current knowledge about the epigenetic mechanisms that deregulate the KEAP1/NRF2 cascade in solid tumors and their potential usefulness as prognostic and predictive molecular markers.
| S-EPMC5872633 | biostudies-literature
Project description:The metabolic pathways fueling tumor growth have been well characterized, but the specific impact of transforming events on network topology and enzyme essentiality remains poorly understood. To this end, we performed combinatorial CRISPR-Cas9 screens on a set of 51 carbohydrate metabolism genes that represent glycolysis and the pentose phosphate pathway (PPP). This high-throughput methodology enabled systems-level interrogation of metabolic gene dispensability, interactions, and compensation across multiple cell types. The metabolic impact of specific combinatorial knockouts was validated using 13C and 2H isotope tracing, and these assays together revealed key nodes controlling redox homeostasis along the KEAP-NRF2 signaling axis. Specifically, targeting KEAP1 in combination with oxidative PPP genes mitigated the deleterious effects of these knockouts on growth rates. These results demonstrate how our integrated framework, combining genetic, transcriptomic, and flux measurements, can improve elucidation of metabolic network alterations and guide precision targeting of metabolic vulnerabilities based on tumor genetics.
| S-EPMC5819357 | biostudies-literature
Project description:NRF2 is a transcription factor that coordinates the antioxidant response in many different tissues, ensuring cytoprotection from endogenous and exogenous stress stimuli. In the kidney, its function is essential in appropriate cellular response to oxidative stress, however its aberrant activation supports progression, metastasis, and resistance to therapies in renal cell carcinoma, similarly to what happens in other nonrenal cancers. While at the moment direct inhibitors of NRF2 are not available, understanding the molecular mechanisms that regulate its hyperactivation in specific tumor types is crucial as it may open new therapeutic perspectives. Here, we focus our attention on renal cell carcinoma, describing how NRF2 hyperactivation can contribute to tumor progression and chemoresistance. Furthermore, we highlight the mechanism whereby the many pathways that are generally altered in these tumors converge to dysregulation of the KEAP1-NRF2 axis.
| S-EPMC7699726 | biostudies-literature
Project description:Nuclear factor E2-related factor 2 (Nrf2) is a key transcription factor that regulates the expression of a number of antioxidant and detoxifying genes that provide cellular protection against various stressors including reactive oxygen species (ROS). Nrf2 activity is tightly regulated by a cytoplasmic inhibitory protein called Kelch-like ECH-associated protein 1 (Keap1). The mechanism that controls Keap1 expression, however, remains poorly understood. In the present study, we demonstrate that microRNA-7 (miR-7), which is highly expressed in the brain, represses Keap1 expression by targeting the 3'-untranslated region (UTR) of its mRNA in human neuroblastoma cells, SH-SY5Y. Subsequently, this event results in an increased Nrf2 activity, as evidenced by an increase in the expression of its transcriptional targets, heme oxygenase 1 (HO-1) and glutamate-cysteine ligase modifier subunit (GCLM), and an enhanced nuclear localization of Nrf2. In addition, miR-7 decreases the intracellular hydroperoxides level and increases the level of reduced form of glutathione, indicative of oxidative stress relief. We also demonstrate that targeted repression of Keap1 and activation of Nrf2 pathway, in part, underlies the protective effects of miR-7 against 1-methyl-4-phenylpyridinium (MPP+)-induced toxicity in SH-SY5Y and differentiated human neural progenitor cells, ReNcell VM. These findings point to a new mechanism by which miR-7 exerts cytoprotective effects by regulating the Nrf2 pathway.
| S-EPMC4684759 | biostudies-literature
Project description:Management of oxaliplatin-induced peripheral neuropathy (OIPN) has proven challenging owing to the concern that any OIPN-preventing agents may also decrease the efficacy of the chemotherapeutic agent and fail to reverse established neuronal damage. Nevertheless, targeting redox signaling pathways constitutes a promising therapy in OIPN and we have previously demonstrated the protective role of nuclear factor erythroid-2 related factor 2 (NRF2) in this disorder. Here, we investigated the protective properties of formononetin (FN), a clinical preparation extract, in OIPN. RNA interference experiments revealed that FN protects against OIPN directly through activation of the NRF2 pathway. Further expression profile sequencing showed that FN exerts its protective effect via the NRF2 downstream-oxaliplatin metabolism enzyme, GSTP1. We also demonstrated that FN does not influence the chemotherapeutic function of oxaliplatin, as NRF2 exhibits a different drug metabolic enzyme activation state downstream in colorectal cell lines than that in neurons. Following synthesis of Bio-FN to screen the target binding proteins, we found that FN selectively binds to His129 and Lys131 in the BTB domain of KEAP1. In vivo experiments revealed that FN-induced activation of the NRF2 signaling pathway alleviated the nociceptive sensations in mice. Our findings highlight a new binding mechanism between KEAP1 and isoflavones for activation of the NRF2 system and suggest that pharmacological or therapeutic activation of the NRF2-GSTP1 axis may serve as an effective strategy to prevent or attenuate the progression of OIPN.
| S-EPMC7451796 | biostudies-literature
Project description:Hypoxia and oxidative stress significantly contribute to breast cancer (BC) progression. Although hypoxia-inducible factor 1α (Hif-1α) is considered a key effector of the cellular response to hypoxia, nuclear factor erythroid 2-related factor 2 (Nrf2), a master antioxidant transcription factor, is a crucial factor essential for Hif-1α-mediated hypoxic responses. Hence, targeting Nrf2 could provide new treatment strategies for cancer therapy. miRNAs are potential regulators of hypoxia-responsive genes. In a quest to identify novel hypoxia-regulated miRNAs involved in the regulation of Nrf2, we found that miR-140-5p significantly affects the expression of Nrf2 under hypoxia. In our study, miR-140-5p expression is downregulated in BC cells under hypoxic conditions. We have identified Nrf2 as a direct target of miR-140-5p, as confirmed by the luciferase assay. Knockdown of miR-140-5p under normoxic conditions significantly enhanced Nrf2/HO-1 signaling and tumor growth, angiogenesis, migration, and invasion in BC. In contrast, overexpression of miR-140-5p under hypoxic conditions revealed opposite results. Further silencing Nrf2 expression mimicked the miR-140-5p-induced anti-tumor effects. Consistent with the knockdown of miR-140-5p in vitro, mice injected with miR-140-5p-KD cells exhibited dramatically reduced miR-140-5p levels, increased Nrf2 levels, and increased tumor growth. In contrast, tumor growth is potently suppressed in mice injected with miR-140-5p-OE cells. Collectively, the above results demonstrate the importance of the Nrf2/HO-1 axis in cancer progression and, thus, targeting Nrf2 by miR-140-5p could be a better strategy for the treatment of Nrf2-driven breast cancer progression.
| S-EPMC8750786 | biostudies-literature