ST8Sia6 expression on tumors inhibits the immune response

肿瘤上 ST8Sia6 的表达抑制免疫反应

• 批准号: 10054986
• 负责人: Virginia Smith Shapiro
• 金额: $ 39.94万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054986
• 关键词: Amaze; Bone Marrow; CTLA4 gene; Cell surface; Cells; Coculture Techniques; Colon Carcinoma; Databases; Development; Down-Regulation; Doxycycline; Engineering; Family; Frequencies; Glycolipids; Growth; HuR protein; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunotherapy; Impairment; Incubated; Innate Immune System; Knockout Mice; Ligands; MC38; Maintenance; Malignant Neoplasms; Mediating; Membrane Glycoproteins; Microsatellite Instability; Modeling; Modification; Mus; PD-1/PD-L1; Patients; Phenotype; Play; Pre-Clinical Model; RNA-Binding Proteins; Regulation; Role; Sialic Acids; Signal Pathway; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Tetanus Helper Peptide; Therapeutic Intervention; Transferase; Transgenes; Transplantation; Tumor Cell Line; Tumor-associated macrophages; anti-PD-L1 therapy; cancer immunotherapy; cancer type; cell growth; conditional knockout; glycosylation; immune activation; immune checkpoint blockade; immunoregulation; in vivo; in vivo Model; lymph nodes; mRNA Stability; macrophage; mouse model; neoplastic cell; novel; overexpression; programmed cell death ligand 1; programmed cell death protein 1; receptor; recruit; response; sialic acid binding Ig-like lectin; sialylation; success; targeted treatment; tumor; tumor growth; tumorigenic

Checkpoint blockade, which targets inhibitory receptors that suppress successful T cell responses to tumors, demonstrates the critical role that the immune response plays against cancer. However, not all cancers respond to immunotherapy or checkpoint blockade targeting PD-1 or CTLA-4 on T cells. For example, the majority of patients with colon cancer do not respond to checkpoint inhibitor monotherapy, which is effective in only 4% of patients with microsatellite instability. Thus, many tumors may target other inhibitory receptors or different components of the immune system to block it from mounting an effective response. One family of inhibitory receptors on immune cells is the Siglec family, which recognize ligands with sialic acid modifications on cell surface glycoproteins or glycolipids. There are twenty eukaryotic sialic acid transferases, each of which differ in their preferred linkage, targets and number of sialic acids added. It has been long recognized that tumors alter the type and frequency of glycosylation and sialic acid on the cell surface. In particular, increased incorporation of sialic acid is frequently observed in cancer, although the function of hyper-sialylation in promoting and sustaining tumor growth is not well understood. Interestingly, using the COSMIC database, we found that while 389 human tumors over-expressed the sialic acid transferase ST8Sia6, none under-expressed ST8Sia6; this indicates a strong selective advantage for tumors with high ST8Sia6, although the function of ST8Sia6 in cancer is not known. We demonstrated that ST8Sia6 overexpression in either MC38 or B16-F10 tumor cell lines accelerated tumor growth in mice. Tumor associated macrophages (TAMs) in ST8Sia6- expressing tumors possessed an M2-like phenotype, as compared to a M1-like phenotype in tumors formed from the parental MC38 or B16-F10 tumor cell lines that lack ST8Sia6 expression. We demonstrated that ST8Sia6 generates ligands for the inhibitory Siglec, Siglec-E, whose expression is restricted to innate immune cells. The growth advantage of ST8Sia6-expressing tumor cells was lost when injected into Siglec-E knockout mice, demonstrating that the primary effect of ST8Sia6 overexpression is on inhibition of the immune response of the host rather than an intrinsic effect on cell growth. We have developed a novel cre-dependent, dox- regulatable ST8Sia6 transgene to study the effect of ST8Sia6 in spontaneous tumor models. Overexpression of ST8Sia6 in a spontaneous model of colon cancer dramatically decreased survival to 2-3 months instead of 6 months, demonstrating the strong effect ST8Sia6 overexpression has on tumor cell growth in vivo. This proposal will examine the function of ST8Sia6 in modulating the immune response to tumors.

检查点阻断，靶向抑制T细胞对肿瘤成功应答的抑制性受体， 证明了免疫反应对癌症的关键作用。然而，并非所有癌症 免疫治疗或检查点阻断靶向T细胞上的PD-1或CTLA-4。比如说 大多数结肠癌患者对检查点抑制剂单药治疗没有反应， 只有4%的患者存在微卫星不稳定性。因此，许多肿瘤可以靶向其他抑制性受体或受体受体结合物。 免疫系统的不同组成部分来阻止它产生有效的反应。One系列 免疫细胞上的抑制性受体是Siglec家族，其识别具有唾液酸修饰的配体 在细胞表面糖蛋白或糖脂上。有二十种真核生物唾液酸转移酶，每一种都 不同之处在于它们优选的连接、目标和添加的唾液酸的数量。人们早就认识到， 肿瘤改变细胞表面糖基化和唾液酸的类型和频率。特别是， 在癌症中经常观察到唾液酸的掺入，尽管高唾液酸化在癌症中的功能是不稳定的。 促进和维持肿瘤生长还没有被很好地理解。有趣的是，使用COSMIC数据库，我们 发现389个人类肿瘤过度表达唾液酸转移酶ST 8 Sia 6，没有一个低表达 ST 8 Sia 6;这表明对于具有高ST 8 Sia 6的肿瘤具有强的选择性优势，尽管ST 8 Sia 6的功能不明显。 ST 8 Sia 6在癌症中的作用尚不清楚。我们证明了ST 8 Sia 6在MC 38或B16-F10中的过表达， 肿瘤细胞系加速小鼠肿瘤生长。ST 8 Sia 6中的肿瘤相关巨噬细胞（TAM）- 与形成的肿瘤中的M1样表型相比，表达肿瘤具有M2样表型， 来自缺乏ST 8 Sia 6表达的亲本MC 38或B16-F10肿瘤细胞系。我们证明了 ST 8 Sia 6产生抑制性Siglec的配体，Siglec-E，其表达限于先天免疫 细胞当注射到Siglec-E敲除细胞中时，表达ST 8 Sia 6的肿瘤细胞的生长优势丧失。 小鼠，证明ST 8 Sia 6过表达的主要作用是抑制免疫应答 而不是对细胞生长的内在影响。我们开发了一种新的依赖于信任的，多克- 可调控的ST 8 Sia 6转基因以研究ST 8 Sia 6在自发肿瘤模型中的作用。过表达 在结肠癌自发模型中，ST 8 Sia 6的表达将存活期显著降低至2-3个月，而不是6个月。 月，证明了ST 8 Sia 6过表达对体内肿瘤细胞生长的强烈影响。这 该提案将研究ST 8 Sia 6在调节对肿瘤的免疫反应中的功能。