Abstract：
Adult T-cell leukemia/lymphoma (ATLL) is one of the aggressive peripheral T-cell neoplasms with a poor prognosis. Accumulating evidence demonstrates that escape from adaptive immunity is a hallmark of ATLL pathogenesis. However, the mechanisms by which ATLL cells evade natural killer (NK)-cell-mediated immunity have been poorly understood. Here we show that CD48 expression in ATLL cells determines the sensitivity for NK-cell-mediated cytotoxicity against ATLL cells. We performed unbiased genome-wide clustered regularly interspaced short palindromic repeat (CRISPR) screening using 2 ATLL-derived cell lines and discovered CD48 as one of the best-enriched genes whose knockout conferred resistance to YT1-NK cell line-mediated cytotoxicity. The ability of CD48-knockout ATLL cells to evade NK-cell effector function was confirmed using human primary NK cells with reduced interferon-γ (IFNγ) induction and degranulation. We found that primary ATLL cells had reduced CD48 expression along with disease progression. Furthermore, other subgroups among aggressive peripheral T-cell lymphomas (PTCLs) also expressed lower concentrations of CD48 than normal T cells, suggesting that CD48 is a key molecule in malignant T-cell evasion of NK-cell surveillance. Thus, this study demonstrates that CD48 expression is likely critical for malignant T-cell lymphoma cell regulation of NK-cell-mediated immunity and provides a rationale for future evaluation of CD48 as a molecular biomarker in NK-cell-associated immunotherapies.
摘要：
成人T细胞白血病/淋巴瘤（ATLL）是预后不良的侵袭性外周T细胞肿瘤之一。越来越多的证据表明，逃避适应性免疫是ATLL发病机理的标志。然而,ATLL细胞逃避自然杀伤（NK）细胞介导的免疫的机制尚不清楚。在这里，我们表明ATLL细胞中的CD48表达决定了NK细胞介导的针对ATLL细胞的细胞毒性的敏感性。我们使用2种ATLL衍生的细胞系进行了无偏差的全基因组成簇规则间隔短回文重复序列（CRISPR）筛选，并发现CD48是最富集的基因之一，其敲除赋予对YT1-NK细胞系介导的细胞毒性的抗性。使用具有减少的干扰素-γ(IFNγ)诱导和脱粒的人原代NK细胞证实了CD48敲除ATLL细胞逃避NK细胞效应子功能的能力。我们发现，随着疾病进展，原代ATLL细胞的CD48表达降低。此外，侵袭性外周T细胞淋巴瘤（PTCL）中的其他亚组也表达低于正常T细胞的CD48浓度，提示CD48是恶性T细胞逃避NK细胞监测的关键分子。因此，这项研究表明,CD48表达可能对恶性T细胞淋巴瘤细胞调节NK细胞介导的免疫至关重要,并为将来评估CD48作为NK细胞相关免疫疗法中的分子生物标志物提供了理论基础.
