Sensitizing Resistant Cancer Cells to T cell-secreted Cytokines
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA879062 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Tumor heterogeneity is a major barrier to cancer therapy, including immunotherapy. Activated T cells can efficiently kill tumor cells following recognition of MHC class I (MHC-I) bound peptides, but this selection pressure favors outgrowth of MHC-I deficient tumor cells. We performed a genome-scale screen to discover alternative pathways for T cell-mediated killing of MHC-I deficient tumor cells. Autophagy and TNF signaling emerged as top pathways, and inactivation of Rnf31 (TNF signaling) and Atg5 (autophagy) sensitized MHC-I deficient tumor cells to apoptosis by T cell-derived cytokines. Mechanistic studies demonstrated that inhibition of autophagy amplified pro-apoptotic effects of cytokines in tumor cells. Antigens from apoptotic MHC-I deficient tumor cells were efficiently cross-presented by dendritic cells, resulting in heightened tumor infiltration by IFNg and TNFa-producing T cells. Tumors with a substantial population of MHC-I deficient cancer cells could be controlled by T cells when both pathways were targeted using genetic or pharmacological approaches.
2022-09-13 | GSE213078 | GEO
Project description:Senescent cells secrete a plethora of factors with potent paracrine signaling capacity. Strikingly, senescence, which acts as a defense against cell transformation, exerts pro-tumorigenic activities through its secretome by promoting numerous tumor-specific features, such as cellular proliferation, epithelial-mesenchymal transition and invasiveness. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the unique activity of activating cell death exclusively in tumor cells. Given that the senescence-associated secretome supports cell transformation, we asked whether factor(s) of this secretome would establish a program required for the acquisition of TRAIL sensitivity. We found that conditioned media from several types of senescent cells (CMS) efficiently sensitized pre-transformed cells to TRAIL, while the same was not observed with normal or immortalized cells. Dynamic transcription profiling analysis of CMS-exposed pre-transformed cells revealed paracrine autoregulatory loop of senescence-associated secretome factors and a dominant role of CMS-induced MYC. Sensitization to TRAIL coincided with MYC upregulation and massive changes in gene regulation. CMS-induced MYC silenced its target gene CFLAR, encoding the apoptosis inhibitor FLIPL, thus leading to the acquisition of TRAIL sensitivity. Altogether, our results reveal that senescent cell-secreted factors exert a TRAIL sensitizing effect on pre-transformed cells by modulating the expression of MYC and CFLAR. Notably, CMS dose-dependent sensitization to TRAIL was observed with TRAIL-insensitive cancer cells and confirmed in co-culture experiments. Dissection and characterization of TRAIL-sensitizing CMS factors and the associated signaling pathway(s) may provide a mechanistic insight in the acquisition of TRAIL sensitivity and lead to novel concepts for the apoptogenic therapy of pre-malignant and TRAIL-resistant tumors. Pre-transformed BJEL cells were incubated with CMS for 0, 1, 3, 6, 8, 16 or 24 h respectively. Total RNA has been extracted from each time point and used for gene expression analysis (Affymetrix Human Gene 1.0 ST Arrays).
2014-01-15 | E-GEOD-49944 | biostudies-arrayexpress
Project description:LncRNA and mRNA expression profiling reveals the molecular mechanism of hyperthermia sensitizing human gastric cancer cisplatin- resistant cell line SGC-7901/DDP
| PRJNA614471 | ENA
Project description:Cancer-associated fibroblasts (CAFs) are an integral part of the tumor microenvironment often linked to drug resistance. Here, we report that CAFs, but not normal fibroblasts, can promote either resistance or unexpected drug sensitization of different lung cancer cells. Using unbiased secretomics, transcriptomics and tyrosine phosphoproteomics, we observed differential expression of several IGF1R signaling components, such as IGF-binding proteins and IGF1/2, and downstream signaling effects on cancer cells by fibroblasts. IGF1/2 treatment or IGFBP5 silencing in CAFs reversed, while addition of exogenous IGFBPs or pharmacological IGF1R inhibitors phenocopied the sensitizing effects. Combining IGF1R and EGFR inhibitors synergized in 2D and 3D models of different drug-resistant and naïve EGFR-mutant lung cancer cells and decreased tumor growth in vivo. These results suggest that multiple resistance mechanisms coexist within the same cancer cells, that CAFs context-dependently cause drug resistance or sensitization, and that understanding both of these differential mechanisms leads to improved therapeutic approaches.
2023-03-11 | PXD023626 | Pride
Project description:Cancer-associated fibroblasts (CAFs) are an integral part of the tumor microenvironment often linked to drug resistance. Here, we report that CAFs, but not normal fibroblasts, can promote either resistance or unexpected drug sensitization of different lung cancer cells. Using unbiased secretomics, transcriptomics and tyrosine phosphoproteomics, we observed differential expression of several IGF1R signaling components, such as IGF-binding proteins and IGF1/2, and downstream signaling effects on cancer cells by fibroblasts. IGF1/2 treatment or IGFBP5 silencing in CAFs reversed, while addition of exogenous IGFBPs or pharmacological IGF1R inhibitors phenocopied the sensitizing effects. Combining IGF1R and EGFR inhibitors synergized in 2D and 3D models of different drug-resistant and naïve EGFR-mutant lung cancer cells and decreased tumor growth in vivo. These results suggest that multiple resistance mechanisms coexist within the same cancer cells, that CAFs context-dependently cause drug resistance or sensitization, and that understanding both of these differential mechanisms leads to improved therapeutic approaches.
2023-03-11 | PXD023692 | Pride
Project description:Taxane resistant breast cancer cells
| PRJEB13235 | ENA
Project description:Senescent cells secrete a plethora of factors with potent paracrine signaling capacity. Strikingly, senescence, which acts as a defense against cell transformation, exerts pro-tumorigenic activities through its secretome by promoting numerous tumor-specific features, such as cellular proliferation, epithelial-mesenchymal transition and invasiveness. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the unique activity of activating cell death exclusively in tumor cells. Given that the senescence-associated secretome supports cell transformation, we asked whether factor(s) of this secretome would establish a program required for the acquisition of TRAIL sensitivity. We found that conditioned media from several types of senescent cells (CMS) efficiently sensitized pre-transformed cells to TRAIL, while the same was not observed with normal or immortalized cells. Dynamic transcription profiling analysis of CMS-exposed pre-transformed cells revealed paracrine autoregulatory loop of senescence-associated secretome factors and a dominant role of CMS-induced MYC. Sensitization to TRAIL coincided with MYC upregulation and massive changes in gene regulation. CMS-induced MYC silenced its target gene CFLAR, encoding the apoptosis inhibitor FLIPL, thus leading to the acquisition of TRAIL sensitivity. Altogether, our results reveal that senescent cell-secreted factors exert a TRAIL sensitizing effect on pre-transformed cells by modulating the expression of MYC and CFLAR. Notably, CMS dose-dependent sensitization to TRAIL was observed with TRAIL-insensitive cancer cells and confirmed in co-culture experiments. Dissection and characterization of TRAIL-sensitizing CMS factors and the associated signaling pathway(s) may provide a mechanistic insight in the acquisition of TRAIL sensitivity and lead to novel concepts for the apoptogenic therapy of pre-malignant and TRAIL-resistant tumors.
2014-01-15 | GSE49944 | GEO
Project description:ImmGen cytokines: Signatures of “common γ-chain” family cytokines
| PRJNA746283 | ENA
Project description:Recombinant cytokines were the first modern immunotherapies to produce durable cures in metastatic cancer, but their application has been hampered by only modest efficacy and limited tolerability. Next-generation cytokine therapies are therefore under development to overcome the biological limitations of native cytokines. By analyzing single-cell transcriptomic data from tumor infiltrating lymphocytes (TIL), we found that components of the Interleukin-18 (IL-18) pathway are upregulated on activated and dysfunctional TIL, suggesting that IL-18 therapy could potentially restore anti-tumor immunity by stimulating these key effector cells. However, recombinant IL-18 therapy has consistently failed to demonstrate anti-tumor efficacy in clinical trials. Here we show that the secreted, high-affinity decoy receptor IL-18BP is frequently upregulated in the tumor microenvironment of diverse human cancers and syngeneic murine tumor models. Using directed evolution, we engineered a ‘decoy-resistant’ IL-18 (DR-18), which maintains signaling potential, but is impervious to binding and inhibition by IL-18BP. In contrast to wild-type IL-18, DR-18 exhibits potent anti-tumor efficacy as monotherapy and in combination with anti-PD-1 checkpoint immunotherapy in multiple tumor models. Mechanistically, DR-18 drives the development of poly-functional effector CD8+ T cells, decreases the prevalence of exhausted CD8+ T cells expressing the transcription factor TOX, and expands the pool of TCF1+ precursor CD8+ T cells. DR-18 also enhances NK cell activity and maturation to effectively treat anti-PD-1 resistant tumors that have lost MHC class I surface expression. Together, these results highlight the IL-18 pathway as a powerful target for immunotherapeutic intervention and implicate the secreted immune checkpoint IL-18BP as an obstacle to effective IL-18 immunotherapy.
2020-06-29 | GSE146609 | GEO