TNFR1 expression on cancer cells is critical for immune escape shaping an immunosuppressive tumor microenvironment
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE334550 | GEO | 2026/08/12
REPOSITORIES: GEO
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Project description:TNFα reportedly mediates multiple protumor and immunosuppressive functions acting on stromal cells in cancer-bearing hosts as a result of enhancing activation immune cell death of T lymphocytes, causing dysfunction of dendritic cells and/or eliciting chemokines which attract myeloid-derived suppressor cells. Experiments performed in transplantable tumors in which we silenced TNFR1 with CRISPR/Cas9 showed the inability of the TNFR1 KO variants to engraft in immunocompetent hosts, whilst engraftment in immunodeficient or CD8 T lymphocyte-depleted mice was preserved. The mechanism was related to secondary inflammatory mediators elicited by TNFα in malignant cells themselves, including CXCR1/2 chemokines and interestingly TNFα itself. As a result, TNFR1 KO variants recruited drastically fewer myeloid-derived suppressor cells into the tumor microenvironment, thus explaining the immune escape of the WT variants. Interestingly, TNFR1-sufficient tumor cells, when co-engrafted with the TNFR1 KO variants, rescued tumorigenicity of the same tumor lesion but not of a distantly implanted TNFR1 KO tumor. Secondary mediators chiefly include CXCR1/2-acting chemokines and prostaglandin E2 synthetase. Similar effects were observed upon knocking-down TNFR1 in a human tumor cell line. Moreover, human TNFR1 KO HT29 variants, when xenografted in immunodeficient mice, released lower levels of CXCL8 (IL-8) and recruited fewer murine myeloid cells into the tumor microenvironment. Analyses of scRNAseq data sets from human solid tumors corroborate the role of TNFR1 on tumor cells to induce secondary proinflammatory mediators. All together, we provide evidence for an essential role of TNFR1 expressed on the surface of tumor cells in immunoscape and further support TNF neutralization in the clinic to improve the efficacy and safety of approved immunotherapy approaches.
2026-08-12 | GSE309029 | GEO
Project description:TNFα reportedly mediates multiple protumor and immunosuppressive functions acting on stromal cells in cancer-bearing hosts as a result of enhancing activation immune cell death of T lymphocytes, causing dysfunction of dendritic cells and/or eliciting chemokines which attract myeloid-derived suppressor cells. Experiments performed in transplantable tumors in which we silenced TNFR1 with CRISPR/Cas9 showed the inability of the TNFR1 KO variants to engraft in immunocompetent hosts, whilst engraftment in immunodeficient or CD8 T lymphocyte-depleted mice was preserved. The mechanism was related to secondary inflammatory mediators elicited by TNFα in malignant cells themselves, including CXCR1/2 chemokines and interestingly TNFα itself. As a result, TNFR1 KO variants recruited drastically fewer myeloid-derived suppressor cells into the tumor microenvironment, thus explaining the immune escape of the WT variants. Interestingly, TNFR1-sufficient tumor cells, when co-engrafted with the TNFR1 KO variants, rescued tumorigenicity of the same tumor lesion but not of a distantly implanted TNFR1 KO tumor. Secondary mediators chiefly include CXCR1/2-acting chemokines and prostaglandin E2 synthetase. Similar effects were observed upon knocking-down TNFR1 in a human tumor cell line. Moreover, human TNFR1 KO HT29 variants, when xenografted in immunodeficient mice, released lower levels of CXCL8 (IL-8) and recruited fewer murine myeloid cells into the tumor microenvironment. Analyses of scRNAseq data sets from human solid tumors corroborate the role of TNFR1 on tumor cells to induce secondary proinflammatory mediators. All together, we provide evidence for an essential role of TNFR1 expressed on the surface of tumor cells in immunoscape and further support TNF neutralization in the clinic to improve the efficacy and safety of approved immunotherapy approaches.
2026-08-12 | GSE309307 | GEO
Project description:Acute pancreatitis (AP) is an inflammatory disorder of the pancreas that can progress to systemic inflammatory response syndrome and multiple organ failure with high mortality. TNFα (tumor necrosis factor-alpha), a key proinflammatory cytokine elevated in early AP, triggers both pancreatic inflammation and acinar cell apoptosis through TNFR1 (tumor necrosis factor-alpha receptor 1) binding. Our study first revealed significant upregulation of TNFα and TNFR1 across three distinct AP animal models. Genetic ablation of Tnfr1 resulted in markedly attenuated AP severity in Tnfr1-/- mice, characterized by reduced inflammatory cell infiltration and decreased tissue inflammation. In bulk RNA analysis identified downregulation of interferon-related genes (Ifi209, Marcksl1, Ifit3, Oas3) in inflammatory cells of Tnfr1-/- mice. Pharmacological inhibition of the TNFα/TNFR1 axis using pomalidomide pretreatment similarly attenuated AP inflammation and significantly suppressed these interferon-associated genes. Notably, therapeutic administration of pomalidomide post-AP induction reproduced these protective effects, confirming the translational potential of targeting this signaling pathway.
2026-08-01 | GSE306650 | GEO
Project description:Acute pancreatitis (AP) is an inflammatory disorder of the pancreas that can progress to systemic inflammatory response syndrome and multiple organ failure with high mortality. TNFα (tumor necrosis factor-alpha), a key proinflammatory cytokine elevated in early AP, triggers both pancreatic inflammation and acinar cell apoptosis through TNFR1 (tumor necrosis factor-alpha receptor 1) binding. However, the predominant pathological mechanism of TNFα/TNFR1 axis in AP - whether primarily mediating inflammatory responses or apoptotic pathways - remains unclear. To elucidate the precise cellular mechanisms through which Tnfr1 deficiency modulates inflammation, we employed scRNA-seq to comprehensively characterize transcriptomic alterations at single-cell resolution.
2026-09-01 | GSE309230 | GEO
Project description:Smac mimetics are considered as promising cancer therapeutics, but little is yet known about how they alter gene expression. In this study we used an unbiased genome-wide expression array to investigate Smac mimetic BV6-induced gene regulation in breast cancer cell lines. Kinetic analysis revealed that BV6 alters gene expression in two waves. The first wave primarily involves NF-κB- and AP-1 families of transcription factors, while the second wave largely depends on tumor necrosis factor receptor 1 (TNFR1) signaling. Interestingly, disrupting auto-/paracrine tumor necrosis factor-α (TNFα)/ (TNFR1) signaling by knockdown of TNFR1 strongly attenuates the BV6-induced second wave of gene expression and upregulation of many pathways including NF-κB signaling, apoptosis and immune signalling, but not MAPK signaling pathways. Consistently, BV6 stimulates phosphorylation of cJun, a marker of MAPK cascade activation, irrespective of the presence or absence of the TNFα blocking antibody Enbrel. We show here in a comprehensive overview that BV6-induced gene expression in breast cancer cells takes place in a time- as well as TNFR1-dependent manner.
2018-02-05 | GSE107912 | GEO
Project description:Tumor microenvironment contains abundant quantities of Tumor necrosis factor alpha (TNFα) secreted by a battery of immune cells. Signal flow through TNFα stimulated TNFR1 signaling, which is supposed to maintain a fine balance between survival and cell-death phenotypes, is often sacrificed in a diseased tissue, such as that of a cancer. Strategies to tilt this balance towards cell-death in a tumor that can help improve the therapeutic efficiency are often remain ineffective due to the cell-to-cell variability in expressing different phenotypes. This variability during TNFR1 signaling stems from the heterogeneity in signal flow through intracellular signaling entities that regulate pro-survival and apoptosis responses. This stochastic Boolean dynamic model of TNFR1 signaling focuses on understanding the dynamic cross-talk regulation of apoptosis at single-cell level. We demonstrate with this model that the signal flow path variability can be modulated to enable cells favour apoptosis. We use BM-ProSPR algorithm (GitHub - ganeshIITB/BMProSPR: Codes pertaining to BM-ProSPR) to compute reliable partial state transition graph (pSTG) for the systematic analysis of the dynamical properties of the network at single-cell level (pSTGs of two different conditions are provided as .mat files). Using the pSTG, we derive a comprehensive way to construct ensemble-level dynamics of intracellular signaling entities in order to understand the cross-talk between the pathways (Methods section in manuscript- Time varying conditional probability of finding a node being active). Model analysis juxtaposed with the experimental observations revealed that NFκB and PI3K transient responses guide XIAP to coordinate the crucial dynamic cross-talk between the pro-survival and apoptotic arms at the single-cell level. Model predicted ~31% increase in apoptosis can be achieved by arresting Comp1-IKK* activity. In summary, the analysis of TNFR1 signaling network model provides insights into
1. What are the central regulators for regulating phenotypic response at single-cell level?
2. How do these regulators coordinate the cross-talk between the pathways of different phenotypes?
3. How do the ensemble-level signal flow paths shift towards a phenotype by arresting an entity that regulates the central regulators’ levels?
2025-04-22 | MODEL2504180001 | BioModels
Project description:Cellular FLICE-inhibitory protein (cFLIP) prevents the development of dermatitis by blocking TNFα-dependent apoptosis of keratinocytes. However, it is unclear whether TNFα-independent signal might also contribute to the development of dermatitis in epidermis-specific Cflar-deficient (Cflar) mice. Here we show that Cflar;Tnfrsf1a-/- mice were born at the expected Mendelian ratio, but developed severe dermatitis and succumbed soon after birth. While keratinocytes still died by apoptosis, expression of epidermal differentiation markers, such as Loricrin, Filaggrin, and Keratin (Krt)10, but not Krt5 were severely downregulated in the skin of Cflar;Tnfrsf1a-/- mice at both mRNA and protein levels. Conversely, inflammatory cytokines, such as interleukin (IL)-6 and Il17a were elevated in the skin of Cflar ;Tnfrsf1a-/- mice. Treatment of primary keratinocytes with IL-6, to a lesser extent IL-17A suppressed expression of Loricrin, Filaggrin, and Krt10. Together, cFLIP suppresses TNFR1-independent apoptosis of keratinocytes and prevents IL-6-dependent blockade of epidermal differentiation.
2020-04-01 | GSE99379 | GEO
Project description:We have compared mRNA expression in full-thickness mouse colon between wildtype mice and mice with a genetic deletion in tumor necrosis factor receptor 1 (TNFR1, encoded by the Tnfrsf1a gene). This experiment was motivated by our observation that Il10-/- Tnfr1-/- double-knockout mice develop very-early-onset colitis at the time of weaning, significantly earlier than disease onset in Il10-/- single-knockout mice. This suggests that TNFR1 mediates protection from colitis. To understand these protective mechanisms at the transcript level in a non-inflammatory context, we performed transcriptome profiling (mRNA-Seq) on colons from 12-week-old Tnfr1-/- mice, which do not develop colitis, and wildtype littermates. These experiments revealed that an estimated 510 transcripts were upregulated and 377 downregulated in colonic tissue of Tnfr1-/- mice. We aggregated the transcript information to calculate gene expression and performed gene set enrichment analysis to identify signaling pathways altered in Tnfr1-/- mice. When queried against a high-confidence set of 50 signaling pathways, the Tnfr1-/- gene expression profile was associated with reduced mitosis and increased glycolysis, transforming growth factor beta signaling, DNA repair, and reactive oxygen species signaling. Gene ontological analysis classified some of the differentially expressed genes into cytokines, junctional proteins, and transcription factors, but within these groups there was no consensus on the direction of regulation. We also examined how differentially expressed transcripts (called the TNFR1-regulated transcriptome) compared to differentially expressed colonic transcripts from previously collected Tnfr2-/- animals (or the TNFR2-regulated transcriptome, available at the NCBI Gene Expression Omnibus under the accession GSE65408). The raw data were re-analyzed with the current pipeline to enable comparison. There was almost no correlation between TNFR1- and TNFR2-regulated transcripts. Only 30 (~3%) TNFR1-regulated transcripts were also TNFR2-regulated transcripts, and ~4% of the TNFR2-regulated genes were also TNFR1-regulated genes. Of the few co-regulated transcripts, there was a significant negative correlation in their direction of regulation in Tnfr1-/- versus Tnfr2-/- colons. Collectively these results indicate that TNFR1 and TNFR2 have mostly different and opposing effects on gene expression in the mouse colon. MANUSCRIPT ABSTRACT: BACKGROUND & AIMS: Very-early-onset inflammatory bowel disease (VEO-IBD) is a devastating disease beginning in early childhood, refractory to anti-tumor necrosis factor (anti-TNF) therapies, and associated with mutations in the interleukin 10 (IL-10) pathway. Contrary to mainstream clinical practice, cellular and animal studies have shown beneficial roles of TNF signaling in colitis, but how these roles are encoded through TNF’s receptors remains unknown. Here we examined the role of TNF receptor 1 (TNFR1, or p55) in modulating the onset and severity of colitis in the interleukin 10 (IL-10)-deficient mouse model. METHODS: Colitis severity was compared between Il10-/- Tnfr1-/- and Il10-/-- littermate mice at 2-12 weeks of age. To assess dysbiosis as a potential pathogenic mechanism, Il10-/- Tnfr1-/- mice were treated with neomycin and metronidazole and their cecal contents analyzed by 16S rRNA sequencing. Gene expression, barrier function, and epithelial proliferation and apoptosis were examined in adult colitis-free Tnfr1-/- wildtype littermates. RESULTS: In contrast to relatively healthy Il10-/- mice, Il10-/- Tnfr1-/- mice developed severe, antibiotic-treatable colitis shortly after weaning. Microbiotal composition was similar between Il10‑/- Tnfr1-/- mice and Il10-/- littermate controls. Tnfr1-/- mice expressed transcripts associated with reactive oxygen species and DNA repair pathways. Tnfr1-/- mice exhibited focal areas of crypt branching, higher colonic epithelial permeability, and hallmarks of DNA damage. CONCLUSIONS: TNFR1 promotes epithelial homeostasis and regulates commensal exposure. The lack of TNFR1 accelerates the onset and severity of IBD in the absence of tolerogenic signaling (i.e., lack of IL-10). Il10-/- Tnfr1-/- mice may serve as a valuable model of very-early-onset IBD (VEO-IBD).
2019-03-15 | GSE107933 | GEO
Project description:Targeting the TNFα/TNFR1 axis to alleviate inflammation in experimental acute pancreatitis
| PRJNA1311586 | ENA
Project description:Genetic abrogation of TNFR1 inhibits pancreatic cancer growth by increasing dendritic cell number and function, and enhanced anti-tumor immunity.
2024-07-27 | GSE260964 | GEO