Mus musculus strain:C57BL/6
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1015258 | ENA |
REPOSITORIES: ENA
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Project description:PRMT1 suppresses anti-tumor immunity
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Project description:T cell dysfunction is a critical obstacle to productive anti-tumor immunity. Previous work has demonstrated that a subset of dysfunctional CD8+ T cells expresses TCF-1, and that this population sustains the T cell response over time. However, the mechanisms that contribute to the generation and maintenance of TCF-1+ CD8+ T cells remain poorly understood. Here, using a model of lung adenocarcinoma, we demonstrate that TCF-1+ CD8+ T cells are found within both tumor and tumor draining LN (dLN), but phenotypically and functionally differ based on location. In tumors, TCF-1+ CD8+ T cells become dysfunctional with time, are heterogeneous, and decline over the course of progression, while TCF-1+ CD8+ T cells in the dLN remain stable. Blocking egress from the dLN decreased SlamF6+ TCF-1+ CD8+ T cells in tumors, demonstrating that the dLN is a critical reservoir of functional CD8+ T cells. Concomitant with the decline in CD8+ T cells in the tumor, migratory conventional dendritic cell type I (cDC1) numbers decreased in the dLN. Therapeutically, boosting cDC1 numbers and function using Flt3L/anti-CD40 antibody resulted in T cell proliferation within the dLN, an increased SlamF6+ TCF-1+ CD8+ T cells in tumors, and a decreased tumor burden. These data demonstrate the importance of migratory cDC1 cells in boosting TCF-1+ CD8+ T cells in the dLN, and provide rationale for targeting DCs in immunotherapy.
2021-10-01 | GSE182028 | GEO
Project description:We observed that proteasome regulator PSME4 inhibits antigen presentation and reduces cellular inflammation in lung adenocarcinoma. As tumor inflammation and antigenicity are key to anti-tumor immunity, we examined the effect of PSME4 in vivo by injecting mice with either KP1.9 or KP1.9PSME4_KD lung adenocarcinoma. We analyzed the changes in the immune milieu by performing single cell RNA sequencing (sc-RNA seq) of CD45+ cells, 3 weeks following injection of tumor cells. This allowed us to examine the effect of PSME4 on the early immune response to the tumor.
2023-03-04 | E-MTAB-10745 | biostudies-arrayexpress
Project description:Type 1 conventional dendritic cells (cDC1) are required for effective CD8 T cell responses to many viruses and tumors and for effective checkpoint blockade immunotherapy. Recently, cytokines produced in association with certain tumors were reported to impair anti-tumor immune responses by reducing the abundance of cDC1. However, the reported mechanism of this reduction remains unclear, attributed either to reduced cDC1 development or decreased peripheral cDC1 survival. Here we show that tumor-derived IL-6 blocks cDC1 development from both in murine and human systems. We show that mechanism of this blockade is the IL-6-dependent increase in C/EBPβ expression in the common dendritic cell progenitor (CDP). C/EBPβ and NFIL3 compete for binding to sites in the -165 kb Zeb2 enhancer, and support or repress Zeb2 expression respectively. At homeostastis, pre-cDC1 specification occurs upon Nfil3 induction and consequent Zeb2 suppression. However, IL-6 strongly induces C/EBPβ expression in CDPs, thereby preventing normal NFIL3-dependent pre-cDC1 specification. Importantly, the ability of IL-6 to block cDC1 development is dependent on the presence of C/EBPβ binding sites in the -165 kb Zeb2 enhancer, as this effect is lost in Δ1+2+3 mutnat mice in which these binding sites are mutated. These results explain how tumor-associated IL-6 suppresses cDC1 development and suggest therapeutic approaches preventing abnormal C/EBPβ induction in CDPs may help reestablish cDC1 development to enhance anti-tumor immunity.
2023-06-22 | GSE215751 | GEO
Project description:SLC38A2 and glutamine signaling in cDC1 dictate anti-tumor immunity
| PRJNA864050 | ENA
Project description:The model is based on publication:
Mathematical analysis of gefitinib resistance of lung adenocarcinoma caused by MET amplification
Abstract:
Gefitinib, one of the tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR), is effective for treating lung adenocarcinoma harboring EGFR mutation; but later, most cases acquire a resistance to gefitinib. One of the mechanisms conferring gefitinib resistance to lung adenocarcinoma is the amplification of the MET gene, which is observed in 5–22% of gefitinib-resistant tumors. A previous study suggested that MET amplification could cause gefitinib resistance by driving ErbB3-dependent activation of the PI3K pathway. In this study, we built a mathematical model of gefitinib resistance caused by MET amplification using lung adenocarcinoma HCC827-GR (gefitinib resistant) cells. The molecular reactions involved in gefitinib resistance consisted of dimerization and phosphorylation of three molecules, EGFR, ErbB3, and MET were described by a series of ordinary differential equations. To perform a computer simulation, we quantified each molecule on the cell surface using flow cytometry and estimated unknown parameters by dimensional analysis. Our simulation showed that the number of active ErbB3 molecules is around a hundred-fold smaller than that of active MET molecules. Limited contribution of ErbB3 in gefitinib resistance by MET amplification is also demonstrated using HCC827-GR cells in culture experiments. Our mathematical model provides a quantitative understanding of the molecular reactions underlying drug resistance.
2024-09-02 | BIOMD0000000827 | BioModels
Project description:Type 1 conventional dendritic cells (cDC1) are required for effective CD8 T cell responses to many viruses and tumors and for effective checkpoint blockade immunotherapy. Recently, cytokines produced in association with certain tumors were reported to impair anti-tumor immune responses by reducing the abundance of cDC1. However, the reported mechanism of this reduction remains unclear, attributed either to reduced cDC1 development or decreased peripheral cDC1 survival. Here we show that tumor-derived IL-6 blocks cDC1 development from both in murine and human systems. We show that mechanism of this blockade is the IL-6-dependent increase in C/EBPβ expression in the common dendritic cell progenitor (CDP). C/EBPβ and NFIL3 compete for binding to sites in the -165 kb Zeb2 enhancer, and support or repress Zeb2 expression respectively. At homeostastis, pre-cDC1 specification occurs upon Nfil3 induction and consequent Zeb2 suppression. However, IL-6 strongly induces C/EBPβ expression in CDPs and increase C/EBPβ bindings at the -165 kb Zeb2 enhancer, thereby preventing normal NFIL3-dependent pre-cDC1 specification. Importantly, the ability of IL-6 to block cDC1 development is dependent on the presence of C/EBPβ binding sites in the -165 kb Zeb2 enhancer, as this effect is lost in Δ1+2+3 mutnat mice in which these binding sites are mutated. These results explain how tumor-associated IL-6 suppresses cDC1 development and suggest therapeutic approaches preventing abnormal C/EBPβ induction in CDPs may help reestablish cDC1 development to enhance anti-tumor immunity.
2023-06-22 | GSE229271 | GEO
Project description:Immune evasion is an important hallmark of cancer ensured by diverse strategies, including immunosuppression and downregulation of antigen presentation. Here, to restore immunogenicity of cancer cells, we employed the minimal gene regulatory network of highly immunogenic type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen presenting cells (APCs). We showed that enforced expression of PU.1, IRF8 and BATF3 (PIB) was sufficient to induce cDC1 phenotype in 33 cell lines derived from human and mouse hematological and solid tumors. PIB gradually modified the cancer cell transcriptional and epigenetic program imposing global antigen presentation and cDC1 gene signatures within 9 days. cDC1 reprogramming restored the expression of antigen presentation complexes as well as co-stimulatory molecules at the cell surface, leading to the presentation of endogenous antigens on MHC-I, and to CD8+ T cell mediated killing. Functionally, tumor- APCs acquired the ability to uptake and process exogenous proteins and dead cells, secreted inflammatory cytokines and cross-presented antigens to naïve CD8+ T cells. Importantly, tumor-APCs were efficiently generated at the single cell level from primary cancer cells of 7 solid tumors that presented antigens to memory and naïve T-cells, as well as to activated patient-specific intra-tumoral lymphocytes. Alongside antigen presentation, tumor-APCs harboring TP53, KRAS and PTEN mutations showed impaired tumorigenicity in vitro and in vivo. Finally, using in vivo mouse models of melanoma, we showed that intra-tumoral injection of tumor-APCs promoted lymphoid infiltration, delayed tumor growth and increased survival. The anti-tumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors enabling tumor eradication. Our approach combines cDC1’s antigen processing and presenting abilities with endogenous generation of tumor antigens and serves as a platform for the development of novel immunotherapies based on endowed antigen presentation in cancer cells.
2023-10-24 | PXD039789 | Pride
Project description:SLC38A2 and glutamine signaling in cDC1 dictate anti-tumor immunity [array]
| PRJNA864048 | ENA