Targeting hypersialylation in multiple myeloma represents a novel approach to enhance NK cell-mediated tumor responses.
Targeting hypersialylation in multiple myeloma represents a novel approach to enhance NK cell-mediated tumor responses.
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DOI：
10.1182/bloodadvances.2021006805
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发表时间：
2022-06-14
期刊：
影响因子：
7.5
通讯作者：
O'Dwyer, Michael E.
中科院分区：
文献类型：
--
作者：
Daly, John;Sarkar, Subhashis;Natoni, Alessandro;Stark, Jessica C.;Riley, Nicholas M.;Bertozzi, Carolyn R.;Carlsten, Mattias;O'Dwyer, Michael E.
MM中的高唾液酰化促进NK细胞的免疫逃避，但可以通过靶向去唾液酰化或siglece -7的遗传缺失来克服。去硅基化揭开了MM细胞上CD38的表达，增强了CD38靶向单克隆抗体诱导的NK细胞介导的ADCC。异常糖基化是癌症的一个标志，在包括多发性骨髓瘤（MM）在内的几种恶性肿瘤中，高唾液化的肿瘤细胞表面促进了异常的细胞运输和耐药性。此外，高唾液酸化也与促进逃避自然杀伤（NK）细胞介导的免疫监视有关，但迄今尚未涉及MM。在这项研究中，我们探讨了高唾液化在促进NK细胞逃逸中的作用。我们记录了唾液酸衍生的siglec7配体（siglec7l）在原代MM细胞和MM细胞系上的强表达，强调了siglec7 / siglec7l在肿瘤微环境中相互作用的可能性。MM细胞裂解物的相互作用实验显示，PSGL-1是MM细胞中主要的siglec7l。我们发现，使用唾液酸酶和唾液酸转移酶抑制剂（SIA）的去盐化作用，强烈增强NK细胞介导的对MM细胞的细胞毒性。此外，MM细胞去盐化导致CD38的检测增加，CD38是MM中一个已被证实的靶点。在抗CD38单克隆抗体daratumumab治疗后，去盐化增强了NK细胞对CD38+ MM细胞的细胞毒性。此外，我们发现CD38低表达的MM细胞可以用全反式维甲酸（ATRA）、SIA和daratumumab处理，以引发有效的NK细胞毒性反应。最后，我们证明了siglec7ko增强NK细胞对siglec7l + MM细胞的细胞毒性。综上所述，我们的工作表明，MM细胞的脱氮化是一种很有希望的新方法，可以增强NK细胞对MM的疗效，它可以与一线治疗相结合，引发有效的抗MM反应。
Hypersialylation in MM facilitates immune evasion of NK cells but can be overcome by targeted desialylation or genetic deletion of Siglec-7. Desialylation unmasks CD38 expression on MM cells, enhancing NK cell–mediated ADCC induced by CD38 targeting of monoclonal antibodies. Abnormal glycosylation is a hallmark of cancer, and the hypersialylated tumor cell surface facilitates abnormal cell trafficking and drug resistance in several malignancies, including multiple myeloma (MM). Furthermore, hypersialylation has also been implicated in facilitating evasion of natural killer (NK) cell–mediated immunosurveillance but not in MM to date. In this study, we explore the role of hypersialylation in promoting escape from NK cells. We document strong expression of sialic acid-derived ligands for Siglec-7 (Siglec-7L) on primary MM cells and MM cell lines, highlighting the possibility of Siglec-7/Siglec-7L interactions in the tumor microenvironment. Interactomics experiments in MM cell lysates revealed PSGL-1 as the predominant Siglec-7L in MM. We show that desialylation, using both a sialidase and sialyltransferase inhibitor (SIA), strongly enhances NK cell–mediated cytotoxicity against MM cells. Furthermore, MM cell desialylation results in increased detection of CD38, a well-validated target in MM. Desialylation enhanced NK cell cytotoxicity against CD38+ MM cells after treatment with the anti-CD38 monoclonal antibody daratumumab. Additionally, we show that MM cells with low CD38 expression can be treated with all trans-retinoic acid (ATRA), SIA and daratumumab to elicit a potent NK cell cytotoxic response. Finally, we demonstrate that Siglec-7KO potentiates NK cell cytotoxicity against Siglec-7L+ MM cells. Taken together, our work shows that desialylation of MM cells is a promising novel approach to enhance NK cell efficacy against MM, which can be combined with frontline therapies to elicit a potent anti-MM response.
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影响因子：
14.8
作者：
Hudak, Jason E.;Canham, Stephen M.;Bertozzi, Carolyn R.
通讯作者：
Bertozzi, Carolyn R.
通过原位创建的高亲和力顺式配体调节 Siglec-7 信号传导。
影响因子：
18.2
作者：
Hong S;Yu C;Rodrigues E;Shi Y;Chen H;Wang P;Chapla DG;Gao T;Zhuang R;Moremen KW;Paulson JC;Macauley MS;Wu P
通讯作者：
Wu P
影响因子：
11.2
作者：
Bull, Christian;Boltje, Thomas J.;Adema, Gosse J.
通讯作者：
Adema, Gosse J.
DOI：
10.1073/pnas.1409580111
发表时间：
2014-09-30
影响因子：
11.1
作者：
Laubli, Heinz;Pearce, Oliver M. T.;Varki, Ajit
通讯作者：
Varki, Ajit
粘蛋白MUC1通过参与凝集素SIGLEC-9调节肿瘤免疫学微环境。
影响因子：
30.5
作者：
Beatson R;Tajadura-Ortega V;Achkova D;Picco G;Tsourouktsoglou TD;Klausing S;Hillier M;Maher J;Noll T;Crocker PR;Taylor-Papadimitriou J;Burchell JM
通讯作者：
Burchell JM