{"title":"肝内和肝外胆管癌对 NK 细胞溶解的敏感性不同,并通过共同和不同的途径调节 NK 细胞功能。","authors":"Ian C Henrich, Ngan Nguyen","doi":"10.1158/1541-7786.MCR-24-0299","DOIUrl":null,"url":null,"abstract":"<p><p>Cholangiocarcinoma (CCA) is a rare cancer that arises from the bile duct and is broadly classified by the location of the tumor as either intrahepatic (iCCA) or extrahepatic (eCCA). Immunotherapy has revolutionized cancer treatment, yet its utility in CCA has been limited as the tumor microenvironment (TME) in CCA is poorly understood compared to other common cancers. Utilizing previously published transcriptome data, our re-analysis has revealed that CCA has one of the highest relative levels of natural killer (NK) cells, a potent cytotoxic immune cell, compared to other cancers. However, despite iCCA and eCCA having comparable relative levels of NK infiltration, NK cell infiltration only correlated with survival in eCCA patients. Our subsequent investigation revealed that while iCCA and eCCA profoundly altered NK activity, eCCA had a significantly reduced impact on NK functionality. Whereas iCCA was resistant to long-term NK co-culture, eCCA was markedly more sensitive. Moreover, while both iCCA and eCCA dysregulated key NK activating receptors, eCCA co-culture did not impact NKp30 nor NKp44 expression. Furthermore, tumor transcriptome analysis of NKHigh CCA samples revealed modulation of multiple immune and non-immune cell types within the TME. Implications: These studies are the first to investigate how iCCA and eCCA impact NK cell functionality through shared and distinct mechanisms and how elevated NK cell infiltration could shape the CCA TME in a subtype-dependent manner.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1000,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Intra- and Extrahepatic Cholangiocarcinomas Display Differing Sensitivities to NK Cell Lysis and Modulate NK Cell Function Through Shared and Distinct Pathways.\",\"authors\":\"Ian C Henrich, Ngan Nguyen\",\"doi\":\"10.1158/1541-7786.MCR-24-0299\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Cholangiocarcinoma (CCA) is a rare cancer that arises from the bile duct and is broadly classified by the location of the tumor as either intrahepatic (iCCA) or extrahepatic (eCCA). Immunotherapy has revolutionized cancer treatment, yet its utility in CCA has been limited as the tumor microenvironment (TME) in CCA is poorly understood compared to other common cancers. Utilizing previously published transcriptome data, our re-analysis has revealed that CCA has one of the highest relative levels of natural killer (NK) cells, a potent cytotoxic immune cell, compared to other cancers. However, despite iCCA and eCCA having comparable relative levels of NK infiltration, NK cell infiltration only correlated with survival in eCCA patients. Our subsequent investigation revealed that while iCCA and eCCA profoundly altered NK activity, eCCA had a significantly reduced impact on NK functionality. Whereas iCCA was resistant to long-term NK co-culture, eCCA was markedly more sensitive. Moreover, while both iCCA and eCCA dysregulated key NK activating receptors, eCCA co-culture did not impact NKp30 nor NKp44 expression. Furthermore, tumor transcriptome analysis of NKHigh CCA samples revealed modulation of multiple immune and non-immune cell types within the TME. Implications: These studies are the first to investigate how iCCA and eCCA impact NK cell functionality through shared and distinct mechanisms and how elevated NK cell infiltration could shape the CCA TME in a subtype-dependent manner.</p>\",\"PeriodicalId\":19095,\"journal\":{\"name\":\"Molecular Cancer Research\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-10-22\",\"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-24-0299\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1541-7786.MCR-24-0299","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
摘要
胆管癌(CCA)是一种来自胆管的罕见癌症,根据肿瘤位置大致可分为肝内癌(iCCA)和肝外癌(eCCA)。免疫疗法给癌症治疗带来了革命性的变化,但由于与其他常见癌症相比,人们对CCA的肿瘤微环境(TME)知之甚少,因此免疫疗法在CCA中的应用受到了限制。利用以前发表的转录组数据,我们重新分析发现,与其他癌症相比,CCA 的自然杀伤(NK)细胞(一种强效细胞毒性免疫细胞)相对水平最高。然而,尽管iCCA和eCCA的NK浸润相对水平相当,但NK细胞浸润只与eCCA患者的存活率相关。我们随后的研究发现,iCCA 和 eCCA 都会严重改变 NK 的活性,而 eCCA 对 NK 功能的影响则明显降低。iCCA 对长期的 NK 协同培养有抵抗力,而 eCCA 则明显更敏感。此外,虽然 iCCA 和 eCCA 都使关键的 NK 激活受体失调,但 eCCA 协同培养并不影响 NKp30 或 NKp44 的表达。此外,对 NKHigh CCA 样本进行的肿瘤转录组分析显示,TME 中的多种免疫和非免疫细胞类型都发生了改变。意义:这些研究首次探讨了 iCCA 和 eCCA 如何通过共同和不同的机制影响 NK 细胞的功能,以及 NK 细胞浸润的增加如何以亚型依赖的方式塑造 CCA TME。
Intra- and Extrahepatic Cholangiocarcinomas Display Differing Sensitivities to NK Cell Lysis and Modulate NK Cell Function Through Shared and Distinct Pathways.
Cholangiocarcinoma (CCA) is a rare cancer that arises from the bile duct and is broadly classified by the location of the tumor as either intrahepatic (iCCA) or extrahepatic (eCCA). Immunotherapy has revolutionized cancer treatment, yet its utility in CCA has been limited as the tumor microenvironment (TME) in CCA is poorly understood compared to other common cancers. Utilizing previously published transcriptome data, our re-analysis has revealed that CCA has one of the highest relative levels of natural killer (NK) cells, a potent cytotoxic immune cell, compared to other cancers. However, despite iCCA and eCCA having comparable relative levels of NK infiltration, NK cell infiltration only correlated with survival in eCCA patients. Our subsequent investigation revealed that while iCCA and eCCA profoundly altered NK activity, eCCA had a significantly reduced impact on NK functionality. Whereas iCCA was resistant to long-term NK co-culture, eCCA was markedly more sensitive. Moreover, while both iCCA and eCCA dysregulated key NK activating receptors, eCCA co-culture did not impact NKp30 nor NKp44 expression. Furthermore, tumor transcriptome analysis of NKHigh CCA samples revealed modulation of multiple immune and non-immune cell types within the TME. Implications: These studies are the first to investigate how iCCA and eCCA impact NK cell functionality through shared and distinct mechanisms and how elevated NK cell infiltration could shape the CCA TME in a subtype-dependent manner.
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.