Development of a glycopeptide vaccine for cancer metastasis

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治疗针对原发肿瘤，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，肿瘤细胞以一种允许与其微环境不适当相互作用并促进侵袭和全身传播的方式改变其表面分子的呈现。同时，从肿瘤中释放的可溶性因子以旁分泌和内分泌的方式发挥作用，动员基质群，主要由致瘤前骨髓细胞组成，到血液和远处的疾病部位。这些人群通过调节微环境和分泌耐受性细胞因子来促进这些部位转移的建立，以防止抗肿瘤免疫反应。发生在转移性肿瘤细胞上的一种特殊的细胞表面改变是碳水化合物基序列的增加，称为汤姆森-弗里登赖希抗原（t抗原）。我们假设转移细胞通过结合T细胞与转移生态位中的基质群体相互作用

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.