Cancer cell-intrinsic XBP1 mediates immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production
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ABSTRACT:
PROVIDER: PRJNA886642 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21786205_1.fastq.gz | Fastqsanger.gz | |||
| SRR21786205_2.fastq.gz | Fastqsanger.gz | |||
| SRR21786206_1.fastq.gz | Fastqsanger.gz | |||
| SRR21786206_2.fastq.gz | Fastqsanger.gz | |||
| SRR21786207_1.fastq.gz | Fastqsanger.gz |
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Project description:The IRE1α-XBP1 arm of the unfolded protein response (UPR) has emerged as a central orchestrator of malignant progression and immunosuppression in various cancer types. Yet the role of this pathway in non-small cell lung cancer (NSCLC) has remained largely unexplored. Using an RNA-seq based computational XBP1s detection method applied to TCGA datasets, we uncovered that expression of the IRE1a-generated XBP1s mRNA isoform predicts poor survival in NSCLC patients. Ablation of IRE1a in malignant cells delayed tumor progression and extended survival in an XBP1-dependent fashion in mouse models of NSCLC. This protective effect was accompanied by marked alterations in both lymphoid and myeloid intratumoral cell subsets that elicited durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1α activation sustained mPGES-1 expression, enabling production of the immunosuppressive lipid mediator PGE2 in the tumor microenvironment (TME). Accordingly, restoring mPGES-1 expression in IRE1αKO cancer cells rescued normal tumor progression. By identifying the dominant transcriptional networks controlled by IRE1α in mouse lung tumors, we further developed a new gene signature that predicted immune cell infiltration and overall survival in human NSCLC. Hence, our study unveils a key immunoregulatory role for cancer cell-intrinsic IRE1α activation and suggests that targeting this pathway may help enhance anti-tumor immunity in NSCLC.
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Project description:Tumor cell-intrinsic ATP6V0A1 drives immunosuppressive reprogramming in colorectal cancer
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Project description:Tumors evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function. However, it remains unclear how intratumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer (OvCa), an aggressive malignancy refractory to standard treatments and current immunotherapies, induces Endoplasmic Reticulum (ER) stress and activation of the IRE1α-XBP1 arm of the Unfolded Protein Response (UPR)10,11 in T cells to control their mitochondrial respiration and anti-tumor function. XBP1 upregulation in T cells isolated from human OvCa specimens was associated with decreased intratumoral T cell infiltration and reduced IFNG mRNA expression. Malignant ascites fluid obtained from OvCa patients inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, leading to IRE1α/XBP1-driven suppression of mitochondrial activity and IFN- production. Mechanistically, XBP1 induction limited the influx of glutamine necessary to sustain T cell mitochondrial respiration under glucose-deprived conditions by regulating the abundance of glutamine carriers. Restoring N-linked protein glycosylation, abrogating IRE1α-XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to OvCa ascites. XBP1-deficient T cells in the metastatic OvCa milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, OvCa-bearing mice lacking XBP1 selectively in T cells demonstrated superior anti-tumor immunity, delayed malignant progression and increased overall survival. Therefore, controlling ER stress or targeting IRE1α-XBP1 signaling may help restore T cell metabolic fitness and anti-tumor capacity in cancer hosts.
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Project description:The IRE1α-XBP1 arm of the unfolded protein response (UPR) maintains endoplasmic reticulum (ER) homeostasis, but also controls UPR-independent processes such as cytokine production and lipid metabolism. Yet, the physiological consequences of IRE1α-XBP1 activation in immune cells remain largely unexplored. Here, we report that leukocyte-intrinsic IRE1α-XBP1 signaling drives prostaglandin biosynthesis and pain. Transcriptomic analyses revealed that induction of prostaglandin-endoperoxide synthase 2 (Ptgs2/Cox-2) and prostaglandin E synthase (Ptges/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated via pattern recognition receptors. Inducible biosynthesis of prostaglandins, including PGE2, was markedly decreased in myeloid cells lacking IRE1α or XBP1, but not altered in the absence of the two other ER stress sensors PERK and ATF6. Mechanistically, IRE1α-activated XBP1 bound to and directly induced the expression of human PTGS2 and PTGES to enable PGE2 generation. Mice selectively lacking IRE1α-XBP1 in leukocytes, or treated with pharmacological IRE1α inhibitors, failed to induce PGE2 upon challenge with inflammatory stimuli and demonstrated reduced behavioral pain responses in PGE2-dependent models of pain. Our study uncovers an unexpected role for IRE1α-XBP1 as a key mediator of prostaglandin biosynthesis and indicates that targeting this pathway may represent an alternative approach to control pain.
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Project description:XBP1 is the transcriptino factor that is activated by the ER stress. XBP1 is known to induce the ER dexpansion and increase the expression of the ER chaperone genes to prtect the cell from the ER stress. We generated a mouse strain that lacked XBP1 specifically in the mouse intestine by breeding the XBP1flox mice with Villin-cre mice. Here we examined genes that are differentially expressed between WT and XBP1 KO mouse intestine to identify genes that are downstream of XBP1. Experiment Overall Design: Total RNAs were pooled from three mice of indicated genotypes. Microarray experiments were performed by using Affymetrix GeneChip® Mouse Genome 430 2.0 Array in Biopolymers Facility at Harvard Medical School.
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Project description:Natural killer (NK) cells are critical mediators of host immunity against infectious disease and cancer. The intrinsic regulators of NK cells are not fully understood. Here, we demonstrate that the ER stress sensor inositol-requiring enzyme 1 (IRE1α) and its substrate transcription factor X-box-binding protein 1 (XBP1) critically drive NK cell-mediated responses against viral infection and tumors. IRE1α and XBP1 were essential for the robust expansion of activated mouse and human NK cells. Transcriptome analysis revealed the transcription factor c-Myc as a novel and direct target of XBP1 for downstream regulation of NK cell proliferation. Genetic ablation or pharmaceutical blockade of IRE1α downregulated c-Myc, whereas overexpression of XBP1 resulted in c-Myc hyperactivation. NK cells lacking c-Myc demonstrated a functional deficit comparable to IRE1α or XBP1 deficiency. Overall, our study identifies a novel IRE1-XBP1-cMyc axis in NK cell immunity, providing new insight into the host immune response against infection and cancer.
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Project description:XBP1 is the transcriptino factor that is activated by the ER stress. XBP1 is known to induce the ER dexpansion and increase the expression of the ER chaperone genes to prtect the cell from the ER stress. We generated a mouse strain that lacked XBP1 specifically in the mouse intestine by breeding the XBP1flox mice with Villin-cre mice. Here we examined genes that are differentially expressed between WT and XBP1 KO mouse intestine to identify genes that are downstream of XBP1.
2008-07-10 | GSE12038 | GEO
Project description:The roles of V-ATPase subunits in regulating CRC immune evasion remain unclear. By analyzing the Tumor and Immune System Interaction Database (TISIDB) for correlations between V-ATPases subunits and immune activities, we found that subunit ATP6V0A1 was inversely correlated with immune activities, especially with the proportions of effective or memory T cells in colon adenocarcinoma (COAD), suggesting an immunosuppressive role. With Atp6v0a1/ATP6V0A1 knockdown CRC cells and CRC syngeneic and xenograft mouse models, we confirmed that tumor cell-intrinsic ATP6V0A1 promotes the growth of CRC in an immune-dependent manner. To determine the type of immune cells contributing to ATP6V0A1-mediated immune evasion, we used single-cell transcriptome sequencing (sc-RNA seq) to analyze the ATP6V0A1-edited immune microenvironment in murine MC38 tumors. Holistic immune profiles in Atp6v0a1 knockdown and control MC38 tumors were compared. The results showed that Atp6v0a1 interference in MC38 cells increased the percentages of naïve T, effector T, and memory-like T-2 cells in the total T cell population while decreasing the percentages of exhausted T, Treg, and memory-like T-1 cells. Moreover, the percentages of granulocytes, monocytes, and dendritic cells within the myeloid population were increased in Atp6v0a1 knockdown-derived tumors, whereas the percentage of macrophages was decreased. Of all the immune cell subclusters, memory-like T-2 cells exhibited the most significantly increased cell count ratio in shv0a1 tumors vs. control tumors. In addition, memory-like T-2 cells expressed more effector markers than memory-like T-1 cells. These data suggest that MC38-derived ATP6V0A1 induced immunosuppressive tumor microenvironment (TME) and suppression of the effectiveness of memory-like T cells may play important roles in ATP6V0A1-regulated CRC immune evasion. The study provides directions to investigate the roles and mechanisms of ATP6V0A1 regulating anti-tumor immunity and thus shed light on the potential for ATP6V0A1-targeted immunotherapy in CRC.
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