Single-Cell Analysis of the Multicellular Ecosystem in Viral Carcinogenesis by HTLV-1.
Single-Cell Analysis of the Multicellular Ecosystem in Viral Carcinogenesis by HTLV-1.
复制标题
HTLV-1病毒致癌作用中多细胞生态系统的单细胞分析。
DOI：
10.1158/2643-3230.bcd-21-0044
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发表时间：
2021-09
影响因子：
11.2
通讯作者：
Kataoka K
中科院分区：
文献类型：
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作者：
Koya J;Saito Y;Kameda T;Kogure Y;Yuasa M;Nagasaki J;McClure MB;Shingaki S;Tabata M;Tahira Y;Akizuki K;Kamiunten A;Sekine M;Shide K;Kubuki Y;Hidaka T;Kitanaka A;Nakano N;Utsunomiya A;Togashi Y;Ogawa S;Shimoda K;Kataoka K
HTLV-1感染和白血病发生期间免疫改变的高维单细胞景观确定了癌前和恶性t细胞状态的标志，以及伴随的全身免疫状态向髓细胞和免疫抑制的转变。人t细胞白血病病毒1型（HTLV-1）感染细胞的癌前克隆扩增发生在病毒癌变之前。本研究通过基因组测序、单细胞同步转录组测序和T/ b细胞受体测序以及表面蛋白分析来表征HTLV-1感染伴或不伴成人T细胞白血病/淋巴瘤（ATL）的癌前细胞和多细胞生态系统。我们区分HTLV-1感染和白血病发生引起的恶性表型，并解剖具有不同临床行为的恶性细胞的克隆进化。在htlv -1感染的细胞中，调节性t细胞表型与癌前克隆扩增相关。我们还描述了非恶性造血池中病毒和肿瘤相关变化之间的差异，包括肿瘤特异性骨髓增殖。在一个新生成的条件敲除小鼠模型中，再现了ATL中发现的T细胞限制性CD274（编码PD-L1）基因病变，我们证明了T细胞过度表达的PD-L1转移到周围细胞，导致它们的PD-L1上调。我们的发现为多步骤病毒癌变的克隆进化和免疫景观提供了见解。我们的多模态单细胞分析全面剖析了HTLV-1感染伴和不伴白血病进展的外周血细胞和分子改变。该研究不仅揭示了病毒癌变过程中的癌前克隆扩增，而且有助于制定新的htlv -1相关疾病的诊断和治疗策略。
High-dimensional single-cell landscape of immune alterations during HTLV-1 infection and leukemogenesis identifies hallmarks of premalignant and malignant T-cell states and the accompanying shift of systemic immune state toward myeloid and immunosuppressive. Premalignant clonal expansion of human T-cell leukemia virus type-1 (HTLV-1)–infected cells occurs before viral carcinogenesis. Here we characterize premalignant cells and the multicellular ecosystem in HTLV-1 infection with and without adult T-cell leukemia/lymphoma (ATL) by genome sequencing and single-cell simultaneous transcriptome and T/B-cell receptor sequencing with surface protein analysis. We distinguish malignant phenotypes caused by HTLV-1 infection and leukemogenesis and dissect clonal evolution of malignant cells with different clinical behavior. Within HTLV-1–infected cells, a regulatory T-cell phenotype associates with premalignant clonal expansion. We also delineate differences between virus- and tumor-related changes in the nonmalignant hematopoietic pool, including tumor-specific myeloid propagation. In a newly generated conditional knockout mouse model recapitulating T-cell–restricted CD274 (encoding PD-L1) gene lesions found in ATL, we demonstrate that PD-L1 overexpressed by T cells is transferred to surrounding cells, leading to their PD-L1 upregulation. Our findings provide insights into clonal evolution and immune landscape of multistep virus carcinogenesis. Our multimodal single-cell analyses comprehensively dissect the cellular and molecular alterations of the peripheral blood in HTLV-1 infection, with and without progression to leukemia. This study not only sheds light on premalignant clonal expansion in viral carcinogenesis, but also helps to devise novel diagnostic and therapeutic strategies for HTLV-1–related disorders.