COPZ1 depletion in thyroid tumor cells triggers type I IFN response and immunogenic cell death.
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PROVIDER: PRJNA551594 | ENA |
REPOSITORIES: ENA
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Project description:Thyroid carcinoma (TC) is generally associated with good prognosis, nevertheless no effective treatments are available for aggressive forms not cured by current therapies. We previously identified the coatomer protein complex zeta 1 (COPZ1), as a new putative therapeutic target for TC, since its depletion impairs the viability of tumor cells, leads to abortive autophagy, ER stress, unfolded protein response and apoptosis, and reduces the tumor growth of TC xenograft models. In this study, by combining genomic, proteomic and functional approaches, we provided evidence that COPZ1 silencing stimulates a type I IFN-mediated viral mimicry response, boosts the production of several inflammatory molecules and finally induces immunogenic cell death, which, in turn, promotes dendritic cell maturation and subsequent activation of T cells. Collectively, our findings support the notion that COPZ1 targeting can be exploited as a new strategy to kill cancer cells with the subsequent involvement of an anti-tumor immune response.
2020-03-05 | PXD014423 | Pride
Project description:Thyroid carcinoma (TC) is generally associated with good prognosis, nevertheless no effective treatments are available for aggressive forms not cured by current therapies. We previously identified the coatomer protein complex zeta 1 (COPZ1) as a new putative therapeutic target for TC, since its depletion impairs the viability of tumor cells, leads to abortive autophagy, ER stress, unfolded protein response and apoptosis, and reduces the tumor growth of TC xenograft models. By combining genomic, proteomic and functional approaches, we now provide evidence that COPZ1 silencing stimulates a type I IFN-mediated viral mimicry response, boosts the production of several inflammatory molecules and induces immunogenic cell death, which in turn promotes dendritic cell maturation and T cell activation. Collectively, our findings indicate that COPZ1 targeting could be exploited as a new strategy to kill cancer cells while stimulating anti-tumor T cell responses.
2020-09-01 | GSE133485 | GEO
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Project description:Belantamab mafodotin, an antibody-drug conjugate targeting B-cell maturation antigen, has demonstrated significant clinical efficacy in combination therapies for relapsed or refractory multiple myeloma. Belantamab mafodotin exerts therapeutic effects through the cytotoxic action of its payload, monomethyl auristatin F, along with its ability to mediate antibody-induced cell death. Significant long-term clinical responses were previously observed in monotherapy treatment – even in patients undergoing dose holds – suggesting involvement of the adaptive immune system. Here, we show that belantamab mafodotin induces markers of immunogenic and inflammatory cell death in vitro and ex vivo. Belantamab mafodotin monotherapy treatment results in an acute inflammatory response that is detectable in patient serum within 24 hours, with increases in granzyme B, CXCL9, CCL3, and CCL4 linked to response depth. High expression of receptors LRP1 and TLR2 that mediate immunogenic cell death on patients’ monocytoid (monocyte/macrophage) cells suggests an important function of the monocytoid lineage to mediate the observed inflammation and immunogenic cell death cascades. Inflammation is followed by remodeling of the innate and adaptive immune system, with a reduction in immune inhibitory signaling alongside the emergence of a CD4 granzyme B-expressing cell population in patients who are in remission vs those that relapse. The ability of belantamab mafodotin to promote adaptive immune responses in addition to its cytotoxic activity may help explain the durable responses observed in treated patients with relapsed/refractory multiple myeloma, despite dose and schedule modifications.
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Project description:Belantamab mafodotin, an antibody-drug conjugate targeting B-cell maturation antigen, has demonstrated significant clinical efficacy in combination therapies for relapsed or refractory multiple myeloma. Belantamab mafodotin exerts therapeutic effects through the cytotoxic action of its payload, monomethyl auristatin F, along with its ability to mediate antibody-induced cell death. Significant long-term clinical responses were previously observed in monotherapy treatment – even in patients undergoing dose holds – suggesting involvement of the adaptive immune system. Here, we show that belantamab mafodotin induces markers of immunogenic and inflammatory cell death in vitro and ex vivo. Belantamab mafodotin monotherapy treatment results in an acute inflammatory response that is detectable in patient serum within 24 hours, with increases in granzyme B, CXCL9, CCL3, and CCL4 linked to response depth. High expression of receptors LRP1 and TLR2 that mediate immunogenic cell death on patients’ monocytoid (monocyte/macrophage) cells suggests an important function of the monocytoid lineage to mediate the observed inflammation and immunogenic cell death cascades. Inflammation is followed by remodeling of the innate and adaptive immune system, with a reduction in immune inhibitory signaling alongside the emergence of a CD4 granzyme B-expressing cell population in patients who are in remission vs those that relapse. The ability of belantamab mafodotin to promote adaptive immune responses in addition to its cytotoxic activity may help explain the durable responses observed in treated patients with relapsed/refractory multiple myeloma, despite dose and schedule modifications.
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Project description:Immunogenic cell death (ICD) represents a spectacular approach to boosting tumor immunotherapy by inducing an adaptive immune response, and it is urgent to identify effective and safe ICD inducers. Here, we identified a conserved, ICD-related circular RNA-cEmsy/cEMSY by performing a systematic screening utilizing immunogenic cell death models induced by multiple cell stressors in lung adenocarcinoma (LUAD). cEmsy/cEMSY triggers ICD in LUAD both in vitro and in vivo, leading to the release of damage-associated molecular patterns (DAMPs) and promoting T-cell cross-priming by dendritic cells (DCs). Notably, in the immunosuppressive tumor model, intratumoral delivery of in vitro-transcribed cEmsy encapsulated in lipid nanoparticles (LNP) induces a potent anti-tumor immune response, which synergizes with PD-1 blockade to facilitate long-term cancer immunity with no apparent toxicities. Mechanistically, cEmsy/cEMSY facilitates TDP-43 aggregation in mitochondria and leverages mitochondrial DNA leakage, activating the cGAS-STING pathway and initiating an antiviral immune response. Clinically, elevated expression level of cEMSY correlates with enhanced DCs and CD8+ T cell infiltration, and favorable immunotherapy response in LUAD. Hence, cEmsy/cEMSY emerges as a safe and potent ICD inducer, offering a dual advantage as a mechanism-based target and a biomarker for enhancing ICI responses in LUAD treatment.
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Project description:PV-10 triggers immunogenic cell death in head and neck squamous cell carcinoma via endoplasmic reticulum stress and apoptosis
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Project description:Clinical applications of human interferon (IFN)-alpha have met with varying degrees of success. Nevertheless, key molecules in IFN-alpha-induced cell death have not been clearly identified. Our previous study indicated that IFN (alpha, beta and omega) receptor (IFNAR) 1/2- and IFN regulatory factor (IRF) 9-RNA interference (RNAi) completely inhibited the antiproliferative (AP) activity of IFN-alpha in human ovarian adenocarcinoma OVCAR3 cells sensitive to IFN-alpha., followed by transcription of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, IFNAR1/2- and IRF9-RNAi inhibited the gene expression of TRAIL, but not of Fas ligand (FasL), following IFN-alpha treatment. In fact, TRAIL but not FasL inhibited the proliferation of OVCAR3 cells. IFN-alpha notably up-regulated the levels of TRAIL protein in the supernatant and on the membrane of OVCAR3 cells. Following TRAIL signaling, Caspase 8 inhibitor and BH3 interacting domain death agonist (BID)-RNAi significantly abrogated both AP activities of IFN-alpha and TRAIL. Furthermore, BID-RNAi prevented both IFN-alpha and TRAIL from collapsing the mitochondrial membrane potential (Delta Psi m). Finally, we provide important new evidence that BID overexpression led to a major enhancement of both AP activities of IFN-alpha and TRAIL in human lung carcinoma A549 cells resistant to IFN-alpha. Thus, this study suggests that BID is crucial in IFN-alpha-induced cell death, indicating a notable potential to be a targeted therapy for IFN-alpha resistant tumors. Biological replicate samples were created by treating OVCAR3 cells with IFN-alpha2c (n=8); IFNAR1-RNAi and IFN-alpha2c (n=4); IFNAR2-RNAi and IFN-alpha2c (n=5); ISGF3gamma-RNAi and IFN-alpha2c (n=3); and Negative RNAi and IFN-alpha2c (n=3). For analysis, the eight IFN-alpha2c treated OVCAR3 samples were paired with an untreated OVCAR3 control sample. The 15 RNAi treated OVCAR3 samples were paired with a Negative RNAi control sample.
2012-05-21 | E-GEOD-29790 | biostudies-arrayexpress
Project description:Clinical applications of human interferon (IFN)-alpha have met with varying degrees of success. Nevertheless, key molecules in IFN-alpha-induced cell death have not been clearly identified. Our previous study indicated that IFN (alpha, beta and omega) receptor (IFNAR) 1/2- and IFN regulatory factor (IRF) 9-RNA interference (RNAi) completely inhibited the antiproliferative (AP) activity of IFN-alpha in human ovarian adenocarcinoma OVCAR3 cells sensitive to IFN-alpha., followed by transcription of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, IFNAR1/2- and IRF9-RNAi inhibited the gene expression of TRAIL, but not of Fas ligand (FasL), following IFN-alpha treatment. In fact, TRAIL but not FasL inhibited the proliferation of OVCAR3 cells. IFN-alpha notably up-regulated the levels of TRAIL protein in the supernatant and on the membrane of OVCAR3 cells. Following TRAIL signaling, Caspase 8 inhibitor and BH3 interacting domain death agonist (BID)-RNAi significantly abrogated both AP activities of IFN-alpha and TRAIL. Furthermore, BID-RNAi prevented both IFN-alpha and TRAIL from collapsing the mitochondrial membrane potential (Delta Psi m). Finally, we provide important new evidence that BID overexpression led to a major enhancement of both AP activities of IFN-alpha and TRAIL in human lung carcinoma A549 cells resistant to IFN-alpha. Thus, this study suggests that BID is crucial in IFN-alpha-induced cell death, indicating a notable potential to be a targeted therapy for IFN-alpha resistant tumors.
2012-05-22 | GSE29790 | GEO
Project description:Immunogenic cell death inducer cEmsy boosted cancer immunotherapy in lung adenocarcinoma
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