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）：癌症是美国第二大死亡原因，虽然目前大多数癌症疗法都针对原发性肿瘤，但估计 90% 的癌症相关死亡是由于转移过程造成的。在整个过程中，肿瘤细胞改变其表面分子的呈现方式，从而允许与其微环境发生不适当的相互作用，并促进侵袭和全身传播。同时，肿瘤释放的可溶性因子以旁分泌和内分泌方式发挥作用，将基质群体（主要由促肿瘤骨髓细胞组成）动员到血液和远处的疾病部位。这些群体通过调节微环境和分泌耐受性细胞因子来防止抗肿瘤免疫反应，从而促进这些部位转移的建立。转移肿瘤细胞上发生的一种特殊的细胞表面改变是被称为汤姆森-弗里登赖希抗原（T-抗原）的碳水化合物基序的表达增加。我们假设转移细胞通过 T 结合与转移微环境中的基质群体相互作用。 这些基质细胞表面的半乳糖凝集素 3 抗原。因此，该提案的目标有两个：(1) 确定 T 抗原与半乳糖凝集素 3 的结合如何促进与转移微环境中促肿瘤免疫细胞的相互作用，从而诱导耐受性；(2) 开发一种专门针对 T 抗原的转移疫苗，以促进产生高特异性的抗肿瘤免疫反应。与传统疫苗相比，癌症疫苗的开发面临着重大挑战，因为其疫苗种类有限。 形成抗肿瘤免疫反应合适靶标的非自身抗原。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 抗原在大多数癌症中普遍存在，加上其在正常细胞中缺乏表达，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，这使得肿瘤细胞的免疫编辑极具挑战性。在这项工作中，我们将生产基于糖肽的疫苗，并在肺腺癌基因小鼠模型的预防和治疗环境中使用这些疗法。我们期望这项工作将有助于产生一类新的癌症治疗方法，专门针对以下方面的变化： 晚期恶性肿瘤中的糖基化。