CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：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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异常糖基化是癌症的一个标志，高度唾液酸化的肿瘤细胞表面促进了多种恶性肿瘤中的异常细胞运输和耐药性，包括多发性骨髓瘤（MM）。
此外，高度唾液酸化也被认为有助于逃逸自然杀伤（NK）细胞介导的免疫监视，但迄今为止在MM中尚未得到证实。在本研究中，我们探讨了高度唾液酸化在促进逃逸NK细胞中的作用。
我们记录了原代MM细胞和MM细胞系上Siglec-7的唾液酸衍生配体（Siglec-7L）的强表达，突显了肿瘤微环境中Siglec-7/Siglec-7L相互作用的可能性。MM细胞裂解物中的相互作用组学实验揭示PSGL-1是MM中主要的Siglec-7L。
我们表明，使用唾液酸酶和唾液酸转移酶抑制剂（SIA）进行去唾液酸化，可强烈增强NK细胞介导的对MM细胞的细胞毒性。此外，MM细胞去唾液酸化导致CD38的检测增加，CD38是MM中一个经过充分验证的靶点。去唾液酸化增强了抗CD38单克隆抗体daratumumab治疗后NK细胞对CD38+ MM细胞的细胞毒性。
此外，我们表明，CD38低表达的MM细胞可以用全反式维甲酸（ATRA）、SIA和daratumumab处理，以引发强效的NK细胞细胞毒性反应。
最后，我们证明Siglec-7KO增强了NK细胞对Siglec-7L+ MM细胞的细胞毒性。综上所述，我们的工作表明，MM细胞的去唾液酸化是一种有前景的新方法，可增强NK细胞对MM的疗效，并且可以与一线治疗联合以引发强效的抗MM反应。
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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