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，尽管当前大多数癌症疗法针对原发性肿瘤，但据估计，与癌症相关的死亡中有90％是由于转移的过程。在整个过程中，肿瘤细胞以允许与微环境不适当相互作用的方式改变其表面分子的呈现，并促进入侵和全身传播。同时，从肿瘤中释放出的可溶性因子以旁分泌和内分泌时尚的作用，以动员基质种群，主要由促肿瘤的髓样细胞组成，这些细胞主要是疾病的血液和远处的疾病部位。这些人群通过调节微环境和耐受性细胞因子的分泌来促进在这些部位建立转移，以防止抗肿瘤免疫反应。在转移肿瘤细胞上发生的一种特定细胞表面改变是碳水化合物基序的增加，称为Thomsen-Friedenreich抗原（T-抗原）。我们假设转移细胞通过T的结合与转移性小境中的基质种群相互作用 这些基质细胞表面上的抗原至元素3。因此，该提案的目标是双重的：（1）确定T-抗原对乳糖素-3的结合如何促进转移性细分市场中与肿瘤的免疫细胞的相互作用，从而诱导转移疫苗，从而诱导转移疫苗，以靶向t-抗抗原的抗原抗性，以使抗毒素的生产具有抗肿瘤的影响。癌症疫苗的开发代表了对常规疫苗的挑战，这是有限的 构成适合抗肿瘤免疫反应的合适靶标的非抗抗原。此外，通过选择下调或不表达的肿瘤细胞进行免疫修订，靶抗原代表了肿瘤逃生的有效机制。 T-抗原在大多数癌中的无处不在表示，结合其在正常细胞上的表达不足，使其成为理想的疫苗靶标。此外，它的呈现是糖基转移酶复杂网络的产物，而不是一个单独的基因，这使肿瘤细胞的免疫程序极具挑战性。在这项工作中，我们将产生基于糖肽的疫苗，并在肺腺癌的遗传小鼠模型中使用这些治疗剂在预防和治疗环境中。我们预计这项工作将有助于产生新的一类新的癌症治疗剂，这些癌症专门针对改变 晚期恶性肿瘤中的糖基化。