The Tumor Microenvironment Imposes Persistent ATF4 in CD8+ TILs to Obstruct Cancer Control
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ABSTRACT:
PROVIDER: PRJNA1279168 | ENA |
REPOSITORIES: ENA
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Project description:The T cell-intrinsic element that responds to tumor microenvironment (TME) stress to shape CD8+ tumor infiltrating lymphocyte (TIL) fate and function in solid cancers remains elusive. Here we report that the hypoxic TME imprints persistent activity of the central transcriptional node of the integrated stress response (ISR), activating transcription factor 4 (ATF4), in CD8+ TILs that results in metabolic polarity, mitochondrial oxidative stress, and cell death. Chronic ATF4 expression replicated the terminal exhaustion cell state in CD8+ T cells and high Atf4 expression in bulk tumor or peripheral T cells of patients with melanoma predicted poor response to PD-1 inhibition. Genetic or pharmacologic attenuation of ATF4 reduced mitochondrial oxidative stress and promoted viability among CD8+ TILs, enabling complete responses to PD-1 inhibition and conferring protection from re-emergent disease. Our multidisciplinary approach identifies chronic ATF4 activity as a barrier to immune checkpoint inhibitors, positioning ISR therapeutics as novel treatment strategies to improve efficacy of immunotherapy combinations.
2025-06-23 | GSE300172 | GEO
Project description:The solid tumor microenvironment (TME) imprints a compromised metabolic state in tumor infiltrating T cells (TILs) hallmarked by the inability to maintain effective energy synthesis for antitumor function and survival. T cells in the TME must catabolize lipids via mitochondrial fatty acid oxidation (FAO) to supply energy in nutrient stress, and it is established that T cells enriched in FAO are adept at cancer control. However, endogenous TILs and unmodified cellular therapy products fail to sustain bioenergetics in tumors. Using patient samples and mouse models, we reveal that the solid TME imposes perpetual acetyl-CoA carboxylase (ACC) activity, invoking lipid biogenesis and storage in TILs that directly opposes FAO. Using metabolic, lipidomic, and confocal imaging strategies, we find that restricting ACC rewires T cell metabolism, enabling energy maintenance in TME stress. Moreover, limiting ACC activity potentiates a gene and phenotypic program indicative of T cell longevity, engendering T cells with increased survival and polyfunctionality, with the ability to control solid cancer.
2024-05-20 | PXD048393 | Pride
Project description:The solid tumor microenvironment (TME) imprints a compromised metabolic state in tumor infiltrating T cells (TILs) hallmarked by the inability to maintain effective energy synthesis for antitumor function and survival. T cells in the TME must catabolize lipids via mitochondrial fatty acid oxidation (FAO) to supply energy in nutrient stress, and it is established that T cells enriched in FAO are adept at cancer control.However, endogenous TILs and unmodified cellular therapy products fail to sustain bioenergetics in tumors. Using patient samples and mouse models, we reveal that the solid TME imposes perpetual acetyl-CoA carboxylase (ACC) activity, invoking lipid biogenesis and storage in TILs that directly opposes FAO. Using metabolic, lipidomic, and confocal imaging strategies, we find that restricting ACC rewires T cell metabolism, enabling energy maintenance in TME stress. Moreover, limiting ACC activity potentiates a gene and phenotypic program indicative of T cell longevity, engendering T cells with increased survival and polyfunctionality, with the ability to control solid cancer.
2024-03-05 | GSE254000 | GEO
Project description:In this study, we demonstrated that deletion of the activating transcription factor 4 (ATF4) resulted in severely impaired HSC expansion in the fetal liver at E12.5 and E15.5. In contrast, generation of the first HSC population in the aorta-gonad-mesonephros region at E11.5 was not significantly affected. Furthermore, the HSC-supporting ability of both endothelial and stromal cells in fetal liver was significantly compromised in the absence of ATF4. Gene profiling using RNA-seq revealed down-regulated expression of a panel of cytokines in ATF4-/- stromal cells, including angiopoietin-like protein 3 (Angptl3) and vascular endothelial growth factor-A (VEGFA). To investigate the molecular pathways of ATF4 in the stromal cells and LSK cells in the fetal liver.
2015-11-20 | E-GEOD-66381 | biostudies-arrayexpress
Project description:In this study, we demonstrated that deletion of the activating transcription factor 4 (ATF4) resulted in severely impaired HSC expansion in the fetal liver at E12.5 and E15.5. In contrast, generation of the first HSC population in the aorta-gonad-mesonephros region at E11.5 was not significantly affected. Furthermore, the HSC-supporting ability of both endothelial and stromal cells in fetal liver was significantly compromised in the absence of ATF4. Gene profiling using RNA-seq revealed down-regulated expression of a panel of cytokines in ATF4-/- stromal cells, including angiopoietin-like protein 3 (Angptl3) and vascular endothelial growth factor-A (VEGFA). To investigate the molecular pathways of ATF4 in the stromal cells and LSK cells in the fetal liver.
2015-11-20 | E-GEOD-66380 | biostudies-arrayexpress
Project description:Clinical significance of tumor-infiltrating lymphocytes (TILs) was demonstrated in many tumor types. In the clinical trials, immune check point inhibitors showed significant clinical efficacy in some tumor types with high mutation burden such as melanoma, bladder cancer, and smoking-induced lung cancer, while there were little effects in cancers with lower mutation rates such as breast cancer. Recently, selection and adoptive transfer of autologous mutation-specific TILs showed successful regression of metastatic tumors in an estrogen receptor-positive breast cancer patient. In this study, we analyzed gene expression profiles in cultured TILs that are reactive or non reactive against autologous breast cancer cells. We cultured TILs and cancer cells derived from breast tumor tissues obtained from the surgery. Reactivity of TILs against cancer cells was determined by interferon gamma (IFN-γ) ELISA analysis after co-culture of TILs and cancer cells for 24 hours. The total RNA was purified from cultured TILs (post-REP TILs) using RNeasy kits. The gene expression library is generated by Illumina TruSeq RNA library prep kit and sequenced.
2025-06-30 | GSE252437 | GEO
Project description:For additional details see Ebert et al, Identification and Small Molecule Inhibition of an ATF4-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy. Quadriceps femoris muscles were harvested from 22-month-old muscle-specfic ATF4 knockout (ATF4 mKO) mice and littermate controls. mRNA levels in ATF4 mKO muscles were normalized to levels in littermate control muscles.
2015-09-03 | E-GEOD-72658 | biostudies-arrayexpress
Project description:To determine gene expression changes induced by ATF4 overexpression, RNA was isolated from BEAS2B cells after overexpression of ATF4 or negative control. mRNA expression was profiled using Affymetrix Human Gene 1.0 ST Arrays. RNA isolated from BEAS2B cells after overexpression of ATF4 or empty vector was processed and hybridized to Affymetrix Human Gene 1.0 ST Arrays. Experiments were performed in triplicate. Data from the 6 microarrays were used for RMA normalization. RMA normalization was performed in the R statsitical environment using the affy package. A t-test was used to determine the association of gene expression with ATF4 overexpression.
2013-05-01 | E-GEOD-45949 | biostudies-arrayexpress
Project description:Activating Transcription Factor 4 (ATF4) is a transcription factor induced by the integrated stress response (ISR). This experiment is a genome-wide profiling of ATF4-dependent RNA expression in human HAP-1 cells. HAP-1 is a near-haploid human cell line that was derived from KBM-7 cells isolated from a patient with Chronic Myelogenous Leukemia. We analyzed WT and ATF4 KO cells. We induced ATF4 expression by mimicking amino acid starvation with the drug histidinol. RNA expression profiles were generated for WT and ATF4 KO HAP1 cells. ATF4 genes were mutated using Cas9 genome editing technology. Amino acid starvation was mimicked by treating WT and ATF4 KO cells with 2 mM histidinol for 24 hours, which increases ATF4 expression.
2015-08-28 | E-GEOD-69308 | biostudies-arrayexpress
Project description:Transcriptomic profile of sorted CD8+ TILs from Rag1-/- mice 4 days after transferred. Each group has two replicates.
2023-12-06 | GSE222539 | GEO