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PROVIDER: PRJNA1320682 | ENA |
REPOSITORIES: ENA
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Project description:Belantamab Mafodotin Triggers Immune Invigoration in Multiple Myeloma Via Inflammatory and Immunogenic Cell Death [Xenium]
| PRJNA1322471 | ENA
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.
2025-09-14 | GSE307661 | GEO
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.
2025-09-14 | GSE307660 | GEO
Project description:Halting Multiple Myeloma with MALT1 Inhibition: Suppressing BCMA-Induced NF-κB and Inducing Immunogenic Cell Death
| PRJNA1107568 | ENA
Project description:PV-10 triggers immunogenic cell death in head and neck squamous cell carcinoma via endoplasmic reticulum stress and apoptosis
| PRJNA1225284 | ENA
Project description:Proteasome inhibitor bortezomib (BTZ) induces apoptosis in myeloma (MM) cells, and has transformed patient outcome. Using in vitro as well as in vivo immunodeficient and immunocompetent murine MM models, we here show that BTZ also triggers immunogenic cell death (ICD) characterized by exposure of calreticulin (CALR) on dying MM cells, phagocytosis of tumor cells by dendritic cells, and induction of MM specific immunity. We identify a BTZ-triggered specific ICD-gene signature which confers improved outcome in two independent MM patient cohorts. Importantly, BTZ stimulates MM cells immunogenicity via activation of cGAS/STING pathway and production of type-I interferons; and STING agonists significantly potentiate BTZ-induced ICD. Our studies therefore delineate mechanisms whereby BTZ exerts immunotherapeutic activity, and provide the framework for clinical trials of STING agonists with BTZ to induce potent tumor-specific immunity and improve patient outcome in MM.
2021-04-12 | GSE171837 | GEO
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.
2024-10-30 | GSE266364 | GEO
Project description:Pro-inflammatory cytokines were shown to promote growth and survival of cancerous cells. TNF induced RelA:p50 NF-κB dimer via the canonical pathway is thought to link inflammation with cancer. Integrating biochemical and computational studies we identify that deficiency of non-canonical signal transducer p100 triggers a positive autoregulatory loop, which instead perpetuates an alternate RelB:p50 containing NF-κB activity upon TNF treatment. TNF stimulated RelB:p50 dimer is sufficient for mediating NF-κB target gene-expressions and suppressing apoptotic cellular death independent of principal NF-κB subunit RelA. We further demonstrate that activating mutations in non-canonical NF-κB module deplete multiple myeloma cells of p100, thereby, provoking autoregulatory RelB:p50 activation. Finally, autoregulatory control reinforces protracted pro-survival NF-κB response, albeit comprising of RelB:p50, upon TNF priming that protects myeloma cells with dysfunctional p100 from subsequent apoptotic insults. In sum, we present evidence for positive autoregulation mediated through the NF-κB system and its potential involvement in human neoplasm.
2017-06-12 | GSE68615 | GEO
Project description:Disulfiram/Copper induces immunogenic cell death via NPL4 in hepatocellular carcinoma
| PRJNA871352 | ENA
Project description:S4, a sulfonamide drug, has been confirmed to induce apoptosis and autophagy in cancer cells. Immunogenic cell death is a special cell death type which is closely related to apoptosis and autophagy. We performed RNA-seq to determine the impact of S4 on global gene expression profile in LN229 cells. Our results show that S4 induces immunogenic cell death via the response to endoplasmic reticulum stress.
2022-06-13 | GSE205538 | GEO