Genome-wide CRISPR screens identify CD48 defining susceptibility to NK cytotoxicity in peripheral T-cell lymphomas.
Genome-wide CRISPR screens identify CD48 defining susceptibility to NK cytotoxicity in peripheral T-cell lymphomas.
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DOI：
10.1182/blood.2022015646
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发表时间：
2022-11-03
期刊：
影响因子：
20.3
通讯作者：
Nakagawa, Masao
中科院分区：
文献类型：
--
作者：
Chiba, Masahiro;Shimono, Joji;Ishio, Takashi;Takei, Norio;Kasahara, Kohei;Ogasawara, Reiki;Ara, Takahide;Goto, Hideki;Izumiyama, Koh;Otsuguro, Satoko;Perera, Liyanage P.;Hasegawa, Hiroo;Maeda, Michiyuki;Hashino, Satoshi;Maenaka, Katsumi;Teshima, Takanori;Waldmann, Thomas A.;Yang, Yibin;Nakagawa, Masao
成人T细胞白血病/淋巴瘤（ATLL）是一种侵袭性外周T细胞肿瘤，预后差。越来越多的证据表明，逃避适应性免疫是ATLL发病机制的标志。然而，ATLL细胞逃避自然杀伤（NK）细胞介导的免疫的机制知之甚少。在这里，我们表明，CD 48在ATLL细胞的表达决定了NK细胞介导的细胞毒性对ATLL细胞的敏感性。我们使用2种ATLL衍生的细胞系进行了无偏的全基因组成簇规则间隔短回文重复序列（CRISPR）筛选，发现CD 48是最富集的基因之一，其敲除赋予对YT 1-NK细胞系介导的细胞毒性的抗性。使用干扰素-γ（IFNγ）诱导和脱粒减少的人原代NK细胞证实了CD 48敲除ATLL细胞逃避NK细胞效应子功能的能力。我们发现原代ATLL细胞随着疾病进展沿着CD 48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较低浓度的CD 48比正常的T细胞，表明CD 48是一个关键的分子在恶性T细胞逃避NK细胞的监视。因此，这项研究表明，CD 48表达可能是恶性T细胞淋巴瘤细胞调节NK细胞介导的免疫至关重要，并提供了一个理论基础，为未来的评价CD 48作为分子生物标志物在NK细胞相关的免疫治疗。全基因组CRISPR文库筛选将CD 48鉴定为定义ATLL中对NK细胞介导的细胞毒性的易感性的关键分子。与正常T细胞相比，ATLL和其他PTCL的CD 48表达减少，这表明CD 48减少在PTCL发病机制中的作用。
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. Whole-genome CRISPR library screening identified CD48 as a key molecule to define susceptibility to NK-cell–mediated cytotoxicity in ATLL. ATLL and other PTCLs had reduced CD48 expression compared with normal T cells, implicating a role of reduced CD48 in PTCL pathogenesis.
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影响因子：
20.3
作者：
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通讯作者：
Mandelboim O
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作者：
Chapuy B;Stewart C;Dunford AJ;Kim J;Kamburov A;Redd RA;Lawrence MS;Roemer MGM;Li AJ;Ziepert M;Staiger AM;Wala JA;Ducar MD;Leshchiner I;Rheinbay E;Taylor-Weiner A;Coughlin CA;Hess JM;Pedamallu CS;Livitz D;Rosebrock D;Rosenberg M;Tracy AA;Horn H;van Hummelen P;Feldman AL;Link BK;Novak AJ;Cerhan JR;Habermann TM;Siebert R;Rosenwald A;Thorner AR;Meyerson ML;Golub TR;Beroukhim R;Wulf GG;Ott G;Rodig SJ;Monti S;Neuberg DS;Loeffler M;Pfreundschuh M;Trümper L;Getz G;Shipp MA
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Shipp MA
影响因子：
20.3
作者：
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通讯作者：
Long, EO