Division of Molecular, Cellular and Medical Biology, The Laboratory of Tumor Immunology and Immunotherapy, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
Mol Carcinog. 2020 Jul;59(7):713-723. doi: 10.1002/mc.23213. Epub 2020 May 11.
Chimeric antigen receptor (CAR) T-cells treatment demonstrate the increasing and powerful potential of immunotherapeutic strategies, as seen mainly for hematological malignancies. Still, efficient CAR-T cell approaches for the treatment of a broader spectrum of tumors are needed. It has been shown that cancer cells can implement strategies to evade immune response that include the expression of inhibitory ligands, such as hypersialylated proteins (sialoglycans) on their surface. These may be recognized by sialic acid-binding immunoglobulin-type lectins (siglecs) which are surface receptors found primarily on immune cells. In this regard, siglec-7 and -9 are found on immune cells, such as natural killer cells, T-cells, and dendritic cells and they can promote immune suppression when binding to sialic acids expressed on target cells. In the present study, we hypothesized that it is possible to use genetically engineered T-cells expressing siglec-based CARs, enabling them to recognize and eliminate tumor cells, in a non-histocompatibility complex molecule restricted way. Thus, we genetically modified human T-cells with different chimeric receptors based on the exodomain of human siglec-7 and -9 molecules and selected optimal receptors. We then assessed their antitumor activity in vitro demonstrating the recognition of cell lines from different histologies. These results were confirmed in a tumor xenograft model exemplifying the potential of the present approach. Overall, this study demonstrates the benefit of targeting cancer-associated glycosylation patterns using CAR based on native immune receptors and expressed in human primary T-cells.
嵌合抗原受体 (CAR) T 细胞治疗显示出免疫治疗策略的不断增强和强大潜力，主要见于血液系统恶性肿瘤。然而，仍需要有效的 CAR-T 细胞方法来治疗更广泛的肿瘤谱。已经表明，癌细胞可以实施逃避免疫反应的策略，包括在其表面表达抑制性配体，如高唾液酸化蛋白（唾液酸聚糖）。这些可以被唾液酸结合免疫球蛋白型凝集素 (siglec) 识别，后者是主要存在于免疫细胞表面的表面受体。在这方面，siglec-7 和 -9 存在于免疫细胞（如自然杀伤细胞、T 细胞和树突状细胞）上，当与靶细胞上表达的唾液酸结合时，它们可以促进免疫抑制。在本研究中，我们假设可以使用表达基于 siglec 的 CAR 的基因工程 T 细胞，使它们能够以非组织相容性复合体分子限制的方式识别和消除肿瘤细胞。因此，我们用人 siglec-7 和 -9 分子的外结构域基因修饰了不同的嵌合受体，并选择了最佳的受体。然后，我们在体外评估了它们的抗肿瘤活性，证明了对不同组织来源的细胞系的识别。这些结果在肿瘤异种移植模型中得到了证实，证明了本方法的潜力。总的来说，这项研究表明使用基于天然免疫受体并在人原代 T 细胞中表达的 CAR 靶向癌症相关糖基化模式的益处。
