Scott D Varney, Dan A Erkes, Glenn L Mersky, Manal U Mustafa, Vivian Chua, Inna Chervoneva, Timothy J Purwin, Emad Alnemri, Andrew E Aplin
{"title":"Metabolic Inhibition Induces Pyroptosis in Uveal Melanoma.","authors":"Scott D Varney, Dan A Erkes, Glenn L Mersky, Manal U Mustafa, Vivian Chua, Inna Chervoneva, Timothy J Purwin, Emad Alnemri, Andrew E Aplin","doi":"10.1158/1541-7786.MCR-24-0508","DOIUrl":null,"url":null,"abstract":"<p><p>Few treatment options are available for patients with metastatic uveal melanoma. Although the bispecific tebentafusp is FDA approved, immunotherapy has largely failed, likely given the poorly immunogenic nature of uveal melanoma. Treatment options that improve the recognition of uveal melanoma by the immune system may be key to reducing disease burden. We investigated whether uveal melanoma has the ability to undergo pyroptosis, a form of immunogenic cell death. Publicly available patient data and cell line analysis showed that uveal melanoma expressed the machinery needed for pyroptosis, including gasdermins D and E (GSDMD and E), caspases 1, 3, 4, and 8, and ninjurin-1. We induced cleavage of GSDMs in uveal melanoma cell lines treated with metabolic inhibitors. In particular, the carnitine palmitoyltransferase 1 (CPT1) inhibitor, etomoxir, induced propidium iodide uptake, caspase 3 cleavage, and the release of HMGB1 and IL-1β, indicating that the observed cleavage of GSDMs led to pyroptosis. Importantly, a gene signature reflecting CPT1A activity correlated with poor prognosis in patients with uveal melanoma and knockdown of CPT1A also induced pyroptosis. Etomoxir-induced pyroptosis was dependent on GSDME but not on GSDMD, and a pyroptosis gene signature correlated with immune infiltration and improved response to immune checkpoint blockade in a set of patients with uveal melanoma. Together, these data show that metabolic inhibitors can induce pyroptosis in uveal melanoma cell lines, potentially offering an approach to enhance inflammation-mediated immune targeting in patients with metastatic uveal melanoma. Implications: Induction of pyroptosis by metabolic inhibition may alter the tumor immune microenvironment and improve the efficacy of immunotherapy in uveal melanoma.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"350-362"},"PeriodicalIF":4.1000,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1541-7786.MCR-24-0508","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Few treatment options are available for patients with metastatic uveal melanoma. Although the bispecific tebentafusp is FDA approved, immunotherapy has largely failed, likely given the poorly immunogenic nature of uveal melanoma. Treatment options that improve the recognition of uveal melanoma by the immune system may be key to reducing disease burden. We investigated whether uveal melanoma has the ability to undergo pyroptosis, a form of immunogenic cell death. Publicly available patient data and cell line analysis showed that uveal melanoma expressed the machinery needed for pyroptosis, including gasdermins D and E (GSDMD and E), caspases 1, 3, 4, and 8, and ninjurin-1. We induced cleavage of GSDMs in uveal melanoma cell lines treated with metabolic inhibitors. In particular, the carnitine palmitoyltransferase 1 (CPT1) inhibitor, etomoxir, induced propidium iodide uptake, caspase 3 cleavage, and the release of HMGB1 and IL-1β, indicating that the observed cleavage of GSDMs led to pyroptosis. Importantly, a gene signature reflecting CPT1A activity correlated with poor prognosis in patients with uveal melanoma and knockdown of CPT1A also induced pyroptosis. Etomoxir-induced pyroptosis was dependent on GSDME but not on GSDMD, and a pyroptosis gene signature correlated with immune infiltration and improved response to immune checkpoint blockade in a set of patients with uveal melanoma. Together, these data show that metabolic inhibitors can induce pyroptosis in uveal melanoma cell lines, potentially offering an approach to enhance inflammation-mediated immune targeting in patients with metastatic uveal melanoma. Implications: Induction of pyroptosis by metabolic inhibition may alter the tumor immune microenvironment and improve the efficacy of immunotherapy in uveal melanoma.
期刊介绍:
Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.