Roles of CD47 Signaling in Tumor Immunology

CD47 信号转导在肿瘤免疫学中的作用

基本信息

批准号：
10702999
负责人：
david d roberts
金额：
$ 16.3万
依托单位：
DIVISION OF CLINICAL SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10702999
关键词：
Anabolism Antibodies Antigen-Presenting Cells Antigens Biological Markers Blood Cells Blood Vessels CD47 gene CTLA4 gene Cell Cycle Cell Differentiation process Cells Cellular Metabolic Process Chemotherapy and/or radiation Cholesterol Homeostasis Communication Cytotoxic T-Lymphocytes Development Eating Endothelial Cells Epitopes FDA approved Gene Expression Gene set enrichment analysis Growth Hematologic Neoplasms Human Hydrogen Sulfide Immune Immune checkpoint inhibitor Immunity Immunocompetent Immunologic Surveillance Immunosuppression In Vitro Inflammatory Interleukin-2 Malignant Neoplasms Mediating Mediator of activation protein Melanoma Cell Membrane Glycoproteins Modeling Mus NK Cell Activation Natural Killer Cells Patient-Focused Outcomes Patients Phagocytes Phagocytosis Physiological Population Production Prognostic Marker RNA Radiation therapy Receptor Signaling Reporting Role SHPS-1 protein Signal Transduction Solid Neoplasm Surface T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Therapeutic Thrombospondin 1 Tumor Immunity Umbilical vein Untranslated RNA Vascular Endothelial Growth Factors Work adaptive immune response angiogenesis anti-CTLA4 antiviral immunity autocrine cancer cell cell killing cell type checkpoint therapy clinical development cytokine early phase clinical trial extracellular vesicles immune checkpoint improved in vivo insight intercellular communication ipilimumab irradiation lipid metabolism macrophage melanoma neoplastic cell new combination therapies preclinical development preclinical study response side effect targeted cancer therapy targeted treatment therapeutic target transcriptomics translational applications tumor tumor immunology tumor microenvironment

项目摘要

CD47 is a ubiquitously expressed cell surface glycoprotein that functions as a signaling receptor for thrombospondin-1 and as the counter-receptor for signal regulatory protein-alpha (SIRP-alpha). Engaging SIRP-alpha on macrophages inhibits phagocytosis, and CD47 thereby serves as a physiological marker of self. However, elevated CD47 expression on some cancer cells also protects tumors from innate immune surveillance and limits adaptive antitumor immunity via inhibitory SIRP-alpha signaling in antigen presenting cells. CD47 also mediates inhibitory thrombospondin-1 signaling in vascular cells, T cells, and NK cells, and blocking inhibitory CD47 signaling on cytotoxic T cells directly increases tumor cell killing. Therefore, CD47 functions as an innate and adaptive immune checkpoint. These findings have led to the development of antibodies and other therapeutic approaches to block CD47 functions in the tumor microenvironment. Preclinical studies in mice demonstrated that blocking CD47 can limit the growth of hematologic malignancies and solid tumors and enhance the efficacy of conventional chemotherapy, radiation therapy, and some targeted cancer therapies. Humanized CD47 antibodies are showing promise in early clinical trials, but side effects related to enhanced phagocytic clearance of circulating blood cells remain a concern. Approaches to circumvent these include antibody preloading strategies, development of antibodies that recognize tumor-specific epitopes of CD47, SIRP-alpha antibodies, and bivalent antibodies that restrict CD47 blockade to specific tumor cells. Preclinical and clinical development of therapeutics targeting CD47 will include developing strategies to combine these agents with various conventional and targeted therapeutics to improve patient outcome for various cancers. T cells and endothelial cells engage in bidirectional communication that regulates angiogenesis and T cell transmigration. Extracellular vesicles (EVs) mediate intercellular communication by the transfer of bioactive molecules including RNAs. EVs produced by a given cell type are heterogeneous in their RNA content, but it is unclear how specific EV surface markers relate to their functional effects on target cells. Our previous work established that Jurkat T cell EVs bearing CD63, MHC-I, or CD47 surface markers contain distinct noncoding RNA populations. The present study reveals that CD63+ and MHC-I+ EVs from CD47-deficient Jurkat T cells are enriched in small non-coding RNAs relative to EVs from wild-type Jurkat T cells. CD47-deficient Jurkat T cells secrete more CD63+ and MHC-I+ EVs, but MHC-I+ EVs are selectively taken up more by human umbilical vein endothelial cells. Transcriptomics analysis of endothelial cells treated with CD63+ or MHC-I+ EVs showed surface marker- and CD47-dependent changes in gene expression in the target cells. Gene set enrichment analysis identified CD47-dependent, and surface marker-dependent effects of T cell EVs on VEGF and inflammatory signaling, cell cycle, and lipid and cholesterol metabolism. Thus, subsets of T cell EVs differentially regulate endothelial cell metabolism and inflammatory and angiogenic responses.

CD47 是一种普遍表达的细胞表面糖蛋白，充当血小板反应蛋白-1 的信号传导受体和信号调节蛋白-α (SIRP-α) 的反受体。巨噬细胞上的 SIRP-α 会抑制吞噬作用，因此 CD47 可以作为自身的生理标记。然而，一些癌细胞上 CD47 表达升高也可以保护肿瘤免受先天免疫监视，并通过抗原呈递细胞中的抑制性 SIRP-α 信号传导限制适应性抗肿瘤免疫。 CD47 还介导血管细胞、T 细胞和 NK 细胞中的抑制性血小板反应蛋白-1 信号传导，阻断细胞毒性 T 细胞上的抑制性 CD47 信号传导可直接增加肿瘤细胞杀伤力。因此，CD47 充当先天性和适应性免疫检查点。这些发现促进了抗体和其他治疗方法的开发，以阻断肿瘤微环境中的 CD47 功能。对小鼠的临床前研究表明，阻断 CD47 可以限制血液恶性肿瘤和实体瘤的生长，并增强常规化疗、放疗和一些靶向癌症治疗的疗效。人源化 CD47 抗体在早期临床试验中显示出希望，但与增强循环血细胞吞噬清除相关的副作用仍然令人担忧。规避这些问题的方法包括抗体预载策略、开发识别 CD47 肿瘤特异性表位的抗体、SIRP-α 抗体以及将 CD47 封锁限制在特定肿瘤细胞的二价抗体。针对 CD47 的疗法的临床前和临床开发将包括开发将这些药物与各种常规和靶向疗法相结合的策略，以改善各种癌症的患者预后。 T 细胞和内皮细胞进行双向通讯，调节血管生成和 T 细胞迁移。细胞外囊泡 (EV) 通过转移包括 RNA 在内的生物活性分子来介导细胞间通讯。特定细胞类型产生的 EV 的 RNA 含量存在异质性，但尚不清楚特定的 EV 表面标记与其对靶细胞的功能影响有何关系。我们之前的工作表明，带有 CD63、MHC-I 或 CD47 表面标记的 Jurkat T 细胞 EV 包含不同的非编码 RNA 群体。本研究表明，相对于野生型 Jurkat T 细胞的 EV，来自 CD47 缺陷型 Jurkat T 细胞的 CD63+ 和 MHC-I+ EV 富含小非编码 RNA。 CD47 缺陷的 Jurkat T 细胞分泌更多的 CD63+ 和 MHC-I+ EV，但 MHC-I+ EV 被人脐静脉内皮细胞选择性摄取更多。用 CD63+ 或 MHC-I+ EV 处理的内皮细胞的转录组学分析显示靶细胞中基因表达的表面标记和 CD47 依赖性变化。基因集富集分析确定了 T 细胞 EV 对 VEGF 和炎症信号、细胞周期以及脂质和胆固醇代谢的 CD47 依赖性和表面标记依赖性影响。因此，T 细胞 EV 的亚群差异性地调节内皮细胞代谢以及炎症和血管生成反应。