Integrated single cell analysis reveals co-evolution of malignant B cells and tumor micro-environment in transformed follicular lymphoma,Cancer Cell

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Integrated single cell analysis reveals co-evolution of malignant B cells and tumor micro-environment in transformed follicular lymphoma
Cancer Cell ( IF 48.8 ) Pub Date : 2024-06-10 , DOI: 10.1016/j.ccell.2024.05.011
Clémentine Sarkozy ₁ , Shaocheng Wu ₂ , Katsuyoshi Takata ₃ , Tomohiro Aoki ₄ , Susana B Neriah ₃ , Katy Milne ₅ , Talia Goodyear ₅ , Celia Strong ₅ , Tashi Rastogi ₅ , Laura K Hilton ₃ , Daniel Lai ₂ , Laurie H Sehn ₃ , Pedro Farinha ₃ , Brad H Nelson ₆ , Andrew Weng ₇ , Marco Marra ₈ , David W Scott ₃ , Jeffrey W Craig ₉ , Christian Steidl ₁₀ , Andrew Roth ₁₁

Affiliation

Hematology Department, Institut Curie, Saint Cloud, France; University PSL, Inserm U1288, Laboratoire d'Imagerie Translationnelle en Oncologie, 91400 Orsay, France.
Department of Molecular Oncology, British Columbia Cancer, Vancouver, BC, Canada.
Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada.
Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Deeley Research Centre, British Columbia Cancer, Vancouver, BC, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada.
Deeley Research Centre, British Columbia Cancer, Vancouver, BC, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Terry Fox Laboratory, British Columbia Cancer, Vancouver, BC, Canada.
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada; Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer, Vancouver, BC, Canada.
Department of Pathology, University of Virginia Health System, Charlottesville, VA, USA.
Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Department of Molecular Oncology, British Columbia Cancer, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Computer Science, University of British Columbia, Vancouver, BC, Canada.

Histological transformation of follicular lymphoma (FL) to aggressive forms is associated with poor outcome. Phenotypic consequences of this evolution and its impact on the tumor microenvironment (TME) remain unknown. We perform single-cell whole genome sequencing (scWGS) and transcriptome sequencing (scWTS) of 11 paired pre/post-transformation patient samples and scWTS of additional samples from patients without transformation. Our analysis reveals evolutionary dynamics of transformation at single-cell resolution, highlighting a shifting TME landscape, with an emerging immune-cell exhaustion signature, co-evolving with the shifting malignant B phenotype in a regulatory ecosystem. Integration of scWGS and scWTS identifies malignant cell pathways upregulated during clonal tumor evolution. Using multi-color immunofluorescence, we transfer these findings to a TME-based transformation biomarker, subsequently validated in two independent pretreatment cohorts. Taken together, our results provide a comprehensive view of the combined genomic and phenotypic evolution of malignant cells during transformation and shifting crosstalk between malignant cells and the TME.

中文翻译：

综合单细胞分析揭示转化滤泡性淋巴瘤中恶性 B 细胞和肿瘤微环境的共同进化

滤泡性淋巴瘤（FL）组织学转化为侵袭性形式与不良预后相关。这种进化的表型后果及其对肿瘤微环境（TME）的影响仍然未知。我们对 11 配对的转化前/后患者样本进行单细胞全基因组测序 (scWGS) 和转录组测序 (scWTS)，并对来自未转化的患者的其他样本进行 scWTS。我们的分析揭示了单细胞分辨率下转化的进化动力学，突出了 TME 景观的变化，以及新兴的免疫细胞衰竭特征，与监管生态系统中不断变化的恶性 B 表型共同进化。 scWGS 和 scWTS 的整合可识别克隆肿瘤进化过程中上调的恶性细胞途径。使用多色免疫荧光，我们将这些发现转移到基于 TME 的转化生物标志物，随后在两个独立的预处理队列中进行验证。总而言之，我们的结果提供了恶性细胞在转化和转移过程中恶性细胞与 TME 之间的串扰的综合基因组和表型进化的全面视图。

更新日期：2024-06-10

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