ST8Sia6 expression on tumors inhibits the immune response

肿瘤上 ST8Sia6 的表达抑制免疫反应

基本信息

批准号：
10308083
负责人：
Virginia Smith Shapiro
金额：
$ 39.14万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
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/10308083
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

项目摘要

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.

检查点封锁，靶向抑制成功T细胞对肿瘤反应的抑制受体，证明了免疫反应对癌症的关键作用。但是，并非所有癌症对靶向PD-1或CTLA-4在T细胞上的免疫疗法或检查点阻滞作出反应。例如，大多数结肠癌患者对检查点抑制剂单一疗法没有反应，这有效仅4％的微卫星不稳定性患者。因此，许多肿瘤可能针对其他抑制受体或免疫系统的不同组成部分阻止其安装有效的响应。一个家庭免疫细胞上的抑制性受体是Siglec家族，该家族识别唾液酸修饰的配体在细胞表面糖蛋白或糖脂上。有二十个真核唾液酸转移酶，每种他们的首选连锁，添加的唾液酸的靶标和数量有所不同。长期以来已经认识到肿瘤改变了细胞表面上糖基化和唾液酸的类型和频率。特别是增加尽管超归归化的功能在癌症中经常观察到唾液酸的掺入促进和维持肿瘤生长尚不清楚。有趣的是，使用宇宙数据库，我们发现虽然389人肿瘤过表达唾液酸转移酶ST8SIA6，但没有表达不足 ST8SIA6;这表明ST8SIA6的肿瘤具有很强的选择性优势，尽管癌症中的ST8SIA6尚不清楚。我们证明了MC38或B16-F10中的ST8SIA6过表达肿瘤细胞系加速了小鼠的肿瘤生长。 ST8SIA6-中肿瘤相关的巨噬细胞（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ST8SIA6表达的亲本MC38或B16-F10肿瘤细胞系。我们证明了这一点 ST8SIA6生成抑制性Siglec，Siglec-E的配体，其表达仅限于先天免疫细胞。注入SIGLEC-E敲除时，丢失了表达ST8SIA6的肿瘤细胞的生长优势小鼠表明ST8SIA6过表达的主要作用是抑制免疫反应宿主而不是对细胞生长的内在作用。我们已经开发了一种新颖的Cre依赖性Dox- 可调节的ST8SIA6转基因研究ST8SIA6在自发肿瘤模型中的作用。过表达在结肠癌自发模型中的ST8SIA6大幅降低至2-3个月而不是6个月几个月，证明ST8SIA6过表达对体内肿瘤细胞的生长具有强大作用。这建议将检查ST8SIA6在调节肿瘤免疫反应中的功能。