Kane A Foster, Elise Rees, Louise Ainley, Eileen M Boyle, Lydia Lee, Gwennan Ward, Daria Galas-Filipowicz, Anna Mikolajczak, Emma J Lyon, Dylan Jankovic, Jasmine Rahman, Mahima Turakhia, Imran Uddin, Gordon Beattie, Yvette Hoade, Catherine Zhu, James L Reading, Ieuan G Walker, Michael A Chapman, Karthik Ramasamy, Javier Herrero, Benny Chain, Sergio A Quezada, Kwee Yong
{"title":"Tumour-intrinsic features shape T-cell differentiation through myeloma disease evolution","authors":"Kane A Foster, Elise Rees, Louise Ainley, Eileen M Boyle, Lydia Lee, Gwennan Ward, Daria Galas-Filipowicz, Anna Mikolajczak, Emma J Lyon, Dylan Jankovic, Jasmine Rahman, Mahima Turakhia, Imran Uddin, Gordon Beattie, Yvette Hoade, Catherine Zhu, James L Reading, Ieuan G Walker, Michael A Chapman, Karthik Ramasamy, Javier Herrero, Benny Chain, Sergio A Quezada, Kwee Yong","doi":"10.1101/2024.06.22.24309250","DOIUrl":null,"url":null,"abstract":"The haematological malignancy multiple myeloma is associated with skewed T-cell activation and function. T-cell alterations are detectable in asymptomatic myeloma precursor conditions and have the potential to identify precursor patients at imminent risk of progression. However, what myeloma-associated T-cells alterations represent mechanistically, how they relate to tumour burden and gene expression, and what influences high inter-patient variability in immune composition remains unknown. Here, we assembled the largest ever dataset of published and newly-generated single-cell RNA and TCR sequencing of the marrow and blood from patients with myeloma, precursor conditions, and age-matched non-cancer controls. We show myeloma is not associated with T-cell exhaustion and instead defined by a pattern of T-cell differentiation resembling antigen-driven terminal memory differentiation. Myeloma-associated T-cell differentiation was dependent on tumour-intrinsic features including tumour burden and tumour expression of antigen-presentation genes. Expanded TCR clones accumulating in myeloma were not enriched for viral specificity and were detected in effector states in highly infiltrated marrows. Together, these results suggest anti-tumour immunity drives a novel form of cancer-associated T-cell memory differentiation in myeloma.","PeriodicalId":501203,"journal":{"name":"medRxiv - Hematology","volume":"12 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"medRxiv - Hematology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2024.06.22.24309250","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
The haematological malignancy multiple myeloma is associated with skewed T-cell activation and function. T-cell alterations are detectable in asymptomatic myeloma precursor conditions and have the potential to identify precursor patients at imminent risk of progression. However, what myeloma-associated T-cells alterations represent mechanistically, how they relate to tumour burden and gene expression, and what influences high inter-patient variability in immune composition remains unknown. Here, we assembled the largest ever dataset of published and newly-generated single-cell RNA and TCR sequencing of the marrow and blood from patients with myeloma, precursor conditions, and age-matched non-cancer controls. We show myeloma is not associated with T-cell exhaustion and instead defined by a pattern of T-cell differentiation resembling antigen-driven terminal memory differentiation. Myeloma-associated T-cell differentiation was dependent on tumour-intrinsic features including tumour burden and tumour expression of antigen-presentation genes. Expanded TCR clones accumulating in myeloma were not enriched for viral specificity and were detected in effector states in highly infiltrated marrows. Together, these results suggest anti-tumour immunity drives a novel form of cancer-associated T-cell memory differentiation in myeloma.
血液恶性肿瘤多发性骨髓瘤与 T 细胞活化和功能失调有关。在无症状的骨髓瘤前驱体中可检测到 T 细胞的改变,并有可能识别出面临迫在眉睫的恶化风险的前驱体患者。然而,骨髓瘤相关 T 细胞的改变在机理上代表什么,它们与肿瘤负荷和基因表达的关系如何,以及是什么影响了患者间免疫组成的高变异性,这些仍是未知数。在这里,我们对骨髓瘤患者的骨髓和血液、前驱症状以及年龄匹配的非癌症对照组的已发表和新产生的单细胞 RNA 和 TCR 测序数据集进行了汇总,这是迄今为止最大的数据集。我们发现骨髓瘤与 T 细胞衰竭无关,而是由一种类似于抗原驱动的终末记忆分化的 T 细胞分化模式定义的。骨髓瘤相关的T细胞分化取决于肿瘤内在特征,包括肿瘤负荷和肿瘤中抗原递呈基因的表达。骨髓瘤中积累的扩大的TCR克隆并不富含病毒特异性,而且在高度浸润的骨髓中以效应状态被检测到。总之,这些结果表明,抗肿瘤免疫推动了骨髓瘤中一种新型的癌症相关 T 细胞记忆分化。