Immunogenic cell death inducer cEmsy boosted cancer immunotherapy in lung adenocarcinoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1106833 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28866305_1.fastq.gz | Fastqsanger.gz | |||
| SRR28866305_2.fastq.gz | Fastqsanger.gz | |||
| SRR28866306_1.fastq.gz | Fastqsanger.gz | |||
| SRR28866306_2.fastq.gz | Fastqsanger.gz | |||
| SRR28866307_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 66 |
Similar Datasets
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:Single-agent immunotherapy, such as immune checkpoint inhibition, has shown remarkable efficacy in selected cancer entities and individual patients. However, most patients fail to respond. This is likely due to diverse immunosuppressive mechanisms acting in a concerted way to suppress the host anti-tumor immune response reducing the efficacy of single-agent immunotherapy. Combination immunotherapy approaches that are effective in such poorly immunogenic tumors mostly rely on precise knowledge of immunological targets on tumor cells by vaccinations or antibodies engineered to directly target those. Thus, creating a target-agnostic combination immunotherapy that is effective in poorly immunogenic tumors for which an immunological target is not known is a major challenge. We show that combined adoptive cellular therapy (ACT) with lymphokine-activated killer cells (LAKs), cytokine-induced killer cells (CIKs), Vγ9Vδ2-T-cells (γδ-T-cells) and adaptive, tumor-specific T-cells (CTLs) display synergistic anti-tumor treatment effects, which is further enhanced by co-treatment with anti-PD1 antibodies. Most strikingly, combination of this ACT with anti-PD1 antibodies, local immunotherapy of agonists against Toll-like receptor 3, 7 and 9 and pre-ACT lymphodepletion, a protocol we named TRI-IT, eradicates established, poorly immunogenic tumors and induces durable anti-tumor immunity in a variety of poorly immunogenic syngeneic, autochthonous, as well as autologous humanized patient-derived models. Mechanistically, we show that TRI-IT co-activates adaptive cellular and humoral, as well as innate anti-tumor immune responses to mediate its anti-tumor effect without inducing off-target toxicity. Our data demonstrate the efficacy of a target-agnostic combination immunotherapy that eradicates and potentially cures established poorly immunogenic tumors.
2022-10-28 | GSE173107 | GEO
Project description:Many anticancer agents induce apoptosis, mitotic catastrophe or cellular senescence. Here, we report the functional characterization of an experimental inducer of tumor necrosis factor (TNF)-independent necrosis, necrocide-1 (NC1). NC1 (but not its stereoisomer) killed a panel of human cancer cells (but not normal cells) at nanomolar concentrations and with a non-apoptotic, necrotic morphotype, both in vitro and in vivo. NC1-induced killing was not inhibited by caspase blockers, anti-apoptotic BCL2 overexpression or TNFα neutralization, suggesting that NC1 elicits a bona fide necrotic pathway. However, pharmacological or genetic inhibition of necroptosis, pyroptosis and ferroptosis failed to block NC1-mediated cell death. Instead, NC1 elicited reactive oxygen species (ROS) production by mitochondria, and elimination of mitochondrial DNA, quenching of mitochondrial ROS, as well as blockade of mitochondrial permeability transition with cyclosporine A, interfered with NC1-induced cell death. NC1 induced hallmarks of immunogenic cell death incurring calreticulin (CALR) exposure, ATP secretion and high mobility group box 1 (HMGB1) release. Taken together, these data identify a previously uncharacterized signaling cascade leading to an immunogenic variant of mitochondrion-regulated necrosis, supporting the notion that eliciting regulated necrosis may constitute a valid approach for anticancer therapy.
2023-05-01 | GSE226801 | GEO
Project description:A stem-loop RNA RIG-I agonist induces immunogenic death and vascular remodeling to potentiate cancer immunotherapy
| PRJNA1158836 | ENA
Project description:Some chemotherapeutic agents have been found to enhance the antitumor immunity by inducing immunogenic cell death (ICD). The combination of disulfiram (DSF) and copper (Cu) has demonstrated anti-tumor effects in a range of malignancies including hepatocellular carcinoma (HCC). However, the potential of DSF/Cu as an ICD inducer and whether it could enhance the efficacy of immune checkpoint blockade in HCC remains unknown. Here, we showed that DSF/Cu-treated HCC cells exhibited characteristics of ICD in vitro, such as calreticulin (CRT) exposure, ATP secretion, high mobility group box 1 (HMGB1) release. DSF/Cu treated HCC cells elicited significant immune memory in a vaccination assay. DSF/Cu treatment promoted dendritic cell activation and maturation. The combination of DSF/Cu and CD47 blockade further facilitated DC maturation and subsequently enhanced CD8+ T cell cytotoxicity. Mechanically, DSF/Cu promoted the nuclear accumulation and aggregation of nuclear protein localization protein 4 (NPL4) to inhibit the ubiquitin-proteasome system, thus induced endoplasmic reticulum (ER) stress. Inhibition of NPL4 induced ICD-associated damage-associated molecular patterns. Collectively, our findings demonstrated that DSF/Cu induced ICD-mediated immune activation in HCC and enhanced the efficacy of CD47 blockade.
2022-10-19 | GSE211734 | GEO
Project description:Tripartite target-agnostic combination immunotherapy cures established poorly immunogenic tumors
| PRJNA723833 | 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:The induction of immunogenic cell death (ICD) impedes tumor progression via both tumor cell-intrinsic and -extrinsic mechanisms, representing a robust therapeutic strategy. However, ICD-targeted therapy remains to be explored and optimized. Through kinome-wide CRISPR-Cas9 screen, NUAK1 is identified as a potential target. The ICD-provoking effect of NUAK1 inhibition depends on the production of reactive oxygen species (ROS), consequent to the downregulation of NRF2-mediated antioxidant gene expression. Moreover, the mevalonate pathway/cholesterol biosynthesis, activated by XBP1s downstream of ICD-induced endoplasmic reticulum stress, functions as a negative feedback mechanism. Targeting the mevalonate pathway with CRISPR knockout or HMGCR inhibitor simvastatin amplifies NUAK1 inhibition-mediated ICD and antitumor activity, while cholesterol dampers ROS, ICD and therefore tumor suppression. The combination of NUAK1 inhibitor and statin enhances the efficacy of anti-PD-1 therapy. Collectively, our study unveils the promise of blocking the mevalonate-cholesterol pathway in conjunction with ICD-targeted immunotherapy.
2024-12-11 | GSE283933 | 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:The higher immunogenicity of tumors usually predicts favorable therapeutic responses. Tumor antigens dominate the immunogenic character within tumors. We investigated if there was a targetable tumor antigen during immunogenic chemotherapy within lung cancer. Chemotherapy-induced immunogenic senescence was demonstrated using a multi-marker, three-step workflow and RNA-sequencing data. The ability of anti-lung-specific X protein (LUNX) antibody to suppress the survival of senescent lung cancer cells was evaluated in vitro and in vivo using real-time cytotoxicity analysis and xenograft mouse models, respectively. The induction of cellular senescence by immunogenic chemotherapy boosted cell-surface shuttling of LUNX and enhanced the immunogenic features of senescent tumor cells, which sensitized lung cancer cells to anti-LUNX antibody-mediated therapy and contributed to tumor suppression. The immunogenic senescence-mediated anti-tumor response was triggered by the direct action of antibody on tumor cells, strengthened by natural-killer cells through an antibody-dependent cell-mediated cytotoxicity response and, ultimately, led to tumor control. Our findings suggest that LUNX is a lung cancer targetable-immunogenic antigen. The proportion of lung cancers responding to LUNX-targeting therapy could be expanded substantially by immunogenic chemotherapy that induces senescence-associated translocation of LUNX to the plasma membrane.
2024-10-03 | GSE185207 | GEO