Development of a glycopeptide vaccine for cancer metastasis

用于癌症转移的糖肽疫苗的开发

• 批准号: 8781072
• 负责人: Nathan Edward Reticker-Flynn
• 金额: $ 5.15万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2017-08-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8781072
• 关键词: Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Binding; Blood; Blood Vessels; Cancer Vaccine Related Development; Cancer Vaccines; Carbohydrates; Carcinoma; Cause of Death; Cell surface; Cells; Cellular Structures; Cessation of life; Complex; Development; Disease; Disorder by Site; Disseminated Malignant Neoplasm; Distant; Endocrine; Environment; Extracellular Matrix; Galactose Binding Lectin; Galectin 3; Generations; Genes; Genetic; Glycopeptides; Goals; Homeostasis; Immune; Immune Tolerance; Immune response; Immunotherapy; Individual; Inflammatory; Invaded; Leukocytes; Lung Adenocarcinoma; Lymphoid Tissue; Malignant Neoplasms; Mediating; Mediator of activation protein; Myeloid Cells; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Phase; Play; Polysaccharides; Population; Primary Neoplasm; Process; Production; Prophylactic treatment; Proteins; Recruitment Activity; Regulation; Role; Site; Specificity; Staging; Stromal Cells; Surface; Therapeutic; Therapeutic Uses; Thompson-Friedenreich Antigen; Tumor Escape; United States; Vaccines; Viral Tumor Antigens; Work; base; cancer cell; cancer immunotherapy; cancer therapy; conditioning; cytokine; glycosylation; glycosyltransferase; immunogenicity; mouse model; mutant; neoplastic cell; new therapeutic target; overexpression; paracrine; prevent; public health relevance; release factor; screening; therapeutic target; tumor; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): Cancer is the second leading cause of death in the United States, and while most current cancer therapies target the primary tumor, it is estimated that 90% of cancer-associated deaths are due to the process of metastasis. Throughout this process, tumor cells alter their presentation of surface molecules in a manner that permits inappropriate interactions with their microenvironment and promotes invasion and systemic dissemination. Concurrently, soluble factors released from the tumors act in paracrine and endocrine fashions to mobilize stromal populations, consisting largely of pro-tumorigenic myeloid cells, to the blood and distant sites of disease. These populations promote the establishment of metastases in those sites through conditioning of the microenvironment and secretion of tolerogenic cytokines to prevent anti-tumor immune responses. One particular cell- surface alteration that occurs on metastasizing tumor cells is the increased presentation of a carbohydrate motif known as the Thomsen-Friedenreich Antigen (T-Antigen). We hypothesize that metastatic cells interact with stromal populations in the metastatic niche by binding of the T Antigen to galectin-3 on the surfaces of these stromal cells. Thus, goals of this proposal are twofold: (1) to determine how binding of the T-Antigen to galectin-3 promotes interactions with pro- tumorigenic immune cells in the metastatic niche thus inducing tolerance and (2) to develop a metastasis vaccine that specifically targets the T-Antigen to facilitate the production of anti-tumor immune responses with high specificity. The development of cancer vaccines represents significant challenges over that of conventional vaccines in that there exists a limited repertoire of non-self-antigens that form suitable targets for anti-tumor immune responses. Furthermore, immunoediting through the selection of tumor cells that have downregulated, or do not express, the target antigen represents an effective mechanism of escape for the tumors. The ubiquitous representation of the T-Antigen on the majority of carcinomas, combined with its lack of expression on normal cells, make it an ideal vaccine target. Furthermore, that its presentation is the product of complex networks of glycosyltransferases, rather than one individual gene, renders immunoediting by tumor cells extremely challenging. In this work, we will generate glycopeptide-based vaccines and use these therapeutics in both prophylactic and treatment settings in a genetic mouse model of lung adenocarcinoma. We expect that this work will facilitate the generation of a new class of cancer therapeutics that specifically target changes in glycosylation in advanced stage malignancies.

描述（由申请人提供）：癌症是美国的第二大死亡原因，虽然目前大多数癌症治疗靶向原发性肿瘤，但据估计，90%的癌症相关死亡是由于转移过程。在整个过程中，肿瘤细胞以允许与其微环境不适当相互作用的方式改变其表面分子的呈现，并促进侵袭和全身性传播。同时，从肿瘤中释放的可溶性因子以旁分泌和内分泌方式作用，以动员主要由促肿瘤发生的髓样细胞组成的基质群至疾病的血液和远处部位。这些群体通过调节微环境和分泌致耐受性细胞因子以防止抗肿瘤免疫应答来促进这些部位中转移的建立。发生在转移性肿瘤细胞上的一种特定的细胞表面改变是被称为T-抗原（T-抗原）的碳水化合物基序的提呈增加。我们假设转移细胞通过结合T淋巴细胞与转移小生境中的间质细胞相互作用， 基质细胞表面的半乳糖凝集素3抗原。因此，该提议的目标是双重的：（1）确定T-抗原与半乳糖凝集素-3的结合如何促进与转移性小生境中的促肿瘤发生免疫细胞的相互作用，从而诱导耐受性，和（2）开发特异性靶向T-抗原的转移疫苗，以促进产生具有高特异性的抗肿瘤免疫应答。癌症疫苗的发展代表了对传统疫苗的重大挑战，因为存在有限的库 形成抗肿瘤免疫应答的合适靶点的非自身抗原。此外，通过选择下调或不表达靶抗原的肿瘤细胞进行免疫编辑代表了肿瘤逃逸的有效机制。T抗原在大多数癌细胞上的普遍存在，加上其在正常细胞上缺乏表达，使其成为理想的疫苗靶标。此外，其呈递是糖基转移酶的复杂网络的产物，而不是单个基因，使得肿瘤细胞的免疫编辑极具挑战性。在这项工作中，我们将产生基于糖肽的疫苗，并在肺腺癌遗传小鼠模型的预防和治疗环境中使用这些疗法。我们希望这项工作将有助于产生一类新的癌症治疗方法，专门针对癌症的变化。 晚期恶性肿瘤中的糖基化。