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Propafenone facilitates mitochondrial-associated ferroptosis and synergizes with immunotherapy in melanoma

ABSTRACT: Propafenone facilitates mitochondrial-associated ferroptosis and synergizes with immunotherapy in melanoma

PROVIDER: PRJNA1175556 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31057245_1.fastq.gz	Fastqsanger.gz
	SRR31057245_2.fastq.gz	Fastqsanger.gz
	SRR31057246_1.fastq.gz	Fastqsanger.gz
	SRR31057246_2.fastq.gz	Fastqsanger.gz
	SRR31057247_1.fastq.gz	Fastqsanger.gz

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Propafenone facilitates mitochondrial-associated ferroptosis and synergizes with immunotherapy in melanoma

Project description:Despite the successful application of immunotherapy, both innate and acquired resistance are typical in melanoma. Ferroptosis induction appears to be a potential strategy to enhance the effectiveness of immunotherapy. However, the relationship between the status of ferroptosis and the effectiveness of immunotherapy, as well as viable strategies to augment ferroptosis, remain unclear. In this study, through large-scale drug screening of cardiovascular drugs, we identified propafenone, an anti-arrhythmia medication, as capable of synergizing with ferroptosis inducers in melanoma. Furthermore, we observed that propafenone, in combination with RSL3, collaboratively induces mitochondrial-associated ferroptosis. Mechanistically, propafenone transcriptionally upregulates mitochondrial HMOX1 via activation of the JNK/JUN signaling pathway under RSL3 treatment, leading to overloaded ferrous iron and ROS within the mitochondria. In xenograft models, the combination of propafenone with ferroptosis induction led to nearly complete tumor regression. Consistently, propafenone enhances immunotherapy-induced antitumor immunity and tumoral ferroptosis in tumor-bearing mice. Significantly, patients exhibiting high levels of ferroptosis/JUN/HMOX1 exhibited improved efficacy of immunotherapy and prolonged progression-free survival. These findings suggest that propafenone holds promise as a candidate drug for enhancing the efficacy of immunotherapy and other ferroptosis-targeted therapies in the treatment of melanoma.

2024-10-26 | GSE279924 | GEO

The expression profile of miRNA in response to IFN-γ-driven ferroptosis in melanoma

Project description:Anti-PD-1 immunotherapy has been established to be greatly effective in melanoma treatment, but the low response rate and occurrence of treatment resistance significantly hinder its efficacy. Recent studies have demonstrated that IFN-γ secreted by tumor-infiltrating CD8+T cells suppresses the expression of Xc- system to induce ferroptosis of tumor cells. However, whether the escape of tumor cells from ferroptosis facilitates the resistance to immunotherapy and the upstream regulatory mechanism remain elusive. MiRNAs participate in ferroptosis execution and can be delivered systemically by nanoparticle or alternative carriers, through which obvious therapeutic effect on cancer has been obtained. Herein, through RNA sequencing, we first obtained miRNAs expression profile of melanoma cells in IFN-γ-potentiated ferroptosis.

2022-06-29 | GSE186497 | GEO

CD8+ T cells regulate tumor ferroptosis during cancer immunotherapy

Project description:CD8+ T cells activated by cancer immunotherapy execute tumor clearance mainly by inducing cell death through perforin-granzyme- and Fas/Fas ligand-pathways. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent lipid peroxide accumulation. Although it was mechanistically illuminated in vitro, emerging evidence has shown that ferroptosis may be implicated in a variety of pathological scenarios. However, the involvement of ferroptosis in T cell immunity and cancer immunotherapy is unknown. Here, we find that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumor cells, and in turn, increased ferroptosis contributes to the anti-tumor efficacy of immunotherapy. Mechanistically, IFNg released from CD8+ T cells downregulates expression of SLC3A2 and SLC7A11, two subunits of glutamate-cystine antiporter system xc-, restrains tumor cell cystine uptake, and as a consequence, promotes tumor cell lipid peroxidation and ferroptosis. In preclinical models, depletion of cyst(e)ine by cyst(e)inase in combination with checkpoint blockade synergistically enhances T cell-mediated anti-tumor immunity and induces tumor cell ferroptosis. Thus, T cell-promoted tumor ferroptosis is a novel anti-tumor mechanism. Targeting tumor ferroptosis pathway constitutes a therapeutic approach in combination with checkpoint blockade.

2019-03-16 | GSE128392 | GEO

Synthetic RIG-I agonist-mediated cancer immunotherapy synergizes with MAP-Kinase inhibition against BRAF mutated melanoma

Project description:The implementations of targeted molecular therapies and immunotherapy in melanoma vastly improved the therapeutic outcome in patients with limited efficacy of surgical intervention. Nevertheless, a large fraction of melanoma patients still remains refractory or acquires resistance to these new forms of treatment, illustrating a need for improvement. Here we report that the clinically relevant combination of MAP kinase inhibitors Dabrafenib and Trametinib synergizes with RIG-I agonist-induced immunotherapy to kill BRAF-mutated human and mouse melanoma cells. Kinase inhibition did not compromise the agonist-induced innate immune response of the RIG-I pathway in host immune cells. In a melanoma transplantation mouse model, the triple therapy outperformed the individual therapies. Our study suggests that targeted activation of RIG-I with its synthetic ligand 3pRNA could vastly improve tumor control in a substantial fraction of melanoma patients receiving MAP kinase inhibitors.

2024-07-26 | GSE268982 | GEO

Synthetic RIG-I agonist-mediated cancer immunotherapy synergizes with MAP-Kinase inhibition against BRAF mutated melanoma [YUMM1.7]

2024-06-04 | GSE269008 | GEO

Fasting-mimicking diet synergizes with ferroptosis against quiescent, chemotherapy-resistant cells

Project description:Fasting-mimicking diet synergizes with ferroptosis against quiescent, chemotherapy-resistant cells

| PRJNA885828 | ENA

CD8+ T cells regulate tumor ferroptosis during cancer immunotherapy

Project description:CD8+ T cells regulate tumor ferroptosis during cancer immunotherapy

| PRJNA527311 | ENA

Synthetic RIG-I agonist-mediated cancer immunotherapy synergizes with MAP-Kinase inhibition against BRAF mutated melanoma

Project description:Synthetic RIG-I agonist-mediated cancer immunotherapy synergizes with MAP-Kinase inhibition against BRAF mutated melanoma

| PRJNA1119558 | ENA

Proteomics of melanoma response to immunotherapy reveals dependence on mitochondrial function

Project description:Immunotherapy has revolutionized cancer treatment, yet most patients do not respond. Here, we investigated mechanisms of response by deeply profiling the proteome of clinical samples from advanced stage melanoma patients undergoing either tumor infiltrating lymphocytes (TIL)-based or anti-PD1 immunotherapy. Using high-resolution mass spectrometry, we quantified over 10,300 proteins with high accuracy. Statistical analyses revealed higher oxidative phosphorylation and lipid metabolism in responders in both treatments, and identified proteomic signatures for response. Aiming to elucidate the effects of the metabolic state on the immune response, we examined melanoma cells upon metabolic perturbations or Crisp-Cas9 knockouts. These experiments indicated lipid metabolism as a regulatory mechanism that increases melanoma immunogenicity by elevating antigen presentation, thereby affecting the sensitivity to T-cell mediated killing both in-vitro and in-vivo. Altogether, our proteomic analyses revealed novel association between the melanoma metabolic state and the response to immunotherapy, which can be the basis for future improvement of therapeutic response.

2019-07-29 | PXD006003 | Pride

Ferroptosis of tumor-associated neutrophils is immunosuppressive and promotes tumor growth

Project description:Ferroptosis is a non-apoptotic form of regulated cell death triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. The development of the concept of ferroptosis stemmed from an active search for alternatives to apoptosis in cancer cells. Ferroptosis inducers have shown remarkable effectiveness in killing tumor cells in vitro, yet with no obvious success in experimental animal models, with a notable exception of immune-deficient mice 1,2. This suggests the potential poorly understood contribution of ferroptosis on immune cells. Pathologically activated neutrophils (PMN), termed myeloid-derived suppressor cells (PMN-MDSC), are major negative regulators of anti-tumor immunity3-5. Here, we found that PMN-MDSC in the tumor microenvironment (TME), spontaneously die by ferroptosis. While decreasing the presence of PMN-MDSC, ferroptosis induces the release of oxygenated lipids and limits mouse and human T cell activity. In immune-competent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSC, reduces tumor progression, and synergizes with immune checkpoint blockade (ICB) to suppress the tumor growth. In contrast, induction of ferroptosis in immune-competent mice promotes tumor growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSC in the TME that can be pharmacologically modulated to limit tumor progression.

2022-09-24 | GSE213861 | GEO

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