Metabolic inhibition induces pyroptosis in uveal melanoma.

IF 4.1 2区 医学 Q2 CELL BIOLOGY
Scott D Varney, Dan A Erkes, Glenn L Mersky, Manal U Mustafa, Vivian Chua, Inna Chervoneva, Timothy J Purwin, Emad Alnemri, Andrew E Aplin
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引用次数: 0

Abstract

Few treatment options are available for metastatic uveal melanoma (UM) patients. Although the bispecific tebentafusp is FDA-approved, immunotherapy has largely failed, likely given the poorly immunogenic nature of UM. Treatment options that improve the recognition of UM by the immune system may be key to reducing disease burden. We investigated whether UM has the ability to undergo pyroptosis, a form of immunogenic cell death. Publicly available patient data and cell line analysis showed that UM expressed the machinery needed for pyroptosis, including gasdermins D and E (GSDMD and E), caspases 1, 3, 4, and 8 (CASP1, 3, 4, and 8), and ninjurin1 (NINJ1). We induced cleavage of gasdermins in UM cell lines treated with metabolic inhibitors. In particular, the CPT1 inhibitor, etomoxir, induced propidium iodide uptake, caspase 3 cleavage and the release of HMGB1 and IL-1β, indicating that the observed cleavage of gasdermins led to pyroptosis. Importantly, a gene-signature reflecting CPT1A activity correlated with poor prognosis in UM patients and knockdown of CPT1A also induced pyroptosis. Etomoxir-induced pyroptosis was GSDME-dependent, but GSDMD-independent and a pyroptosis gene-signature correlated with immune infiltration and improved response to immune checkpoint blockade in a set of UM patients. Together, these data show that metabolic inhibitors can induce pyroptosis in UM cell lines, potentially offering an approach to enhance inflammation-mediated immune targeting in metastatic UM patients. Implications: Induction of pyroptosis by metabolic inhibition may alter the tumor immune microenvironment and improve the efficacy of immunotherapy in uveal melanoma.

代谢抑制诱导葡萄膜黑色素瘤热下垂。
转移性葡萄膜黑色素瘤(UM)患者的治疗选择很少。尽管双特异性tebentafusp已获得fda批准,但免疫治疗在很大程度上失败了,可能是由于UM的免疫原性较差。改善免疫系统对UM的识别的治疗方案可能是减轻疾病负担的关键。我们研究了UM是否有能力经历焦亡,一种免疫原性细胞死亡的形式。公开的患者数据和细胞系分析表明,UM表达了焦亡所需的机制,包括gasdermins D和E (GSDMD和E), caspases 1、3、4和8 (CASP1、3、4和8)和ninjurin1 (NINJ1)。我们用代谢抑制剂诱导UM细胞系的气真皮分裂。特别是,CPT1抑制剂乙托莫西诱导碘化丙啶摄取、caspase 3裂解以及HMGB1和IL-1β的释放,表明观察到的裂解导致了焦亡。重要的是,反映CPT1A活性的基因标记与UM患者预后不良相关,CPT1A的敲低也会引起焦亡。在一组UM患者中,依托莫西诱导的焦亡依赖于gsdme,但不依赖于gsdmd,并且焦亡基因特征与免疫浸润和对免疫检查点阻断的改善反应相关。总之,这些数据表明,代谢抑制剂可以诱导UM细胞系焦亡,可能为增强转移性UM患者炎症介导的免疫靶向提供了一种方法。意义:通过代谢抑制诱导焦亡可能改变肿瘤免疫微环境,提高免疫治疗葡萄膜黑色素瘤的疗效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Cancer Research
Molecular Cancer Research 医学-细胞生物学
CiteScore
9.90
自引率
0.00%
发文量
280
审稿时长
4-8 weeks
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.
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