GENETICALLY MODIFIED DENDRITIC CELLS FOR INDUCTION OF CANCER IMMUNITY

癌症免疫学中的一个中心问题是设计肿瘤抗原如何 可以用来刺激和激活免疫反应。大多数肿瘤 抗原是自身抗原，可能会诱导免疫耐受，除非 它们被适当地呈现给免疫系统。几乎在每一个 经过系统测试，树突状细胞是最有效的抗原提呈细胞 它们可以刺激和激活辅助性和细胞毒性T细胞，即使在 前体T细胞处于静止状态，并以低频率存在，这是一种情况 这适用于对肿瘤有反应的淋巴细胞。这个项目的目标是 利用树突状细胞作为抗原提呈物的能力 改造它们来呈递肿瘤抗原。因此，这样做的理由是 工作是基于以下三个前提的。(I)树突状细胞 强大的抗原提呈细胞，而肿瘤细胞则不是。(Ii)基因 转移可用于抗原的最佳选择和呈递。 (3)基因转移可在体内产生持续的抗原表达。在……里面 为了测试这个模型，我们将使用定义的肿瘤分化 黑色素瘤模型中酪氨酸家族的抗原和突变型p53 肉瘤模型中的癌蛋白。第一，基因在小鼠体内的转移和 人类树突状细胞“已在初步实验中获得” 将通过测试关于以下方面的不同类型的构造进行优化 转导、稳定表达和抗原提呈的条件 体外和体内。树突状细胞表达的免疫应答 然后将在体外和体内研究肿瘤抗原。战略是 需要打破对肿瘤分化抗原的耐受性。我们有 发现打破耐受性的一种方法是免疫 同源分化抗原诱导对自身抗原的免疫 由肿瘤表达。将使用鼠标模型来测量 同源肿瘤抗原在多大程度上表达和呈递 通过同基因小鼠树突状细胞，可以打破免疫耐受和 诱导肿瘤排斥反应。这些研究将发展临床前的理论基础。 和使用转基因树突状细胞用于 对已确定的癌症抗原进行免疫。

A central problem in cancer immunology is to devise how tumor antigens could be made to stimulate and activate immune responses. Most tumor antigens are self-antigens, and likely induce immune tolerance unless they are appropriately presented to the immune system. In almost every system tested, dendritic cells are the most potent antigen-presenting cells they can stimulate and activate helper and cytotoxic T cells even when precursor T cells are quiescent and present at low frequencies, a situation that applies to tumor-reactive lymphocytes. The goal of this project is to exploit the power of dendritic cells as antigen presenters by engineering them to present tumor antigens. Thus, the rationale for this work is based on the three following premises. (I) Dendritic cells are potent antigen-presenting cells, while tumor cells are not. (ii) Gene transfer can be used for optimal selection and presentations of antigens. (iii) Gene transfer can produce sustained antigen expression in vivo. In order to test this model, we will use a defined tumor differentiation antigen of the tyrosine family in a melanoma model and a mutant p53 oncoprotein in a sarcoma model. First, gene transfer in mouse and human dendritic cells "already achieved in preliminary experiments" will be optimized by testing different types of constructs with respect to conditions of transduction, stable expression, and antigen presentation in vitro and in vivo. The immune response to dendritic cells expressing tumor antigens will then be studied in vitro and in vivo. Strategies are needed to break tolerance to tumor differentiation antigens. We have found that one approach to breaking tolerance is immunization with homologous differentiation antigen to induce immunity to the self antigen expressed by tumors. Mouse models will be used in order to measure to what extent a homologous tumor antigen, expressed in and presented by syngeneic mouse dendritic cells, can break immune tolerance and induce tumor rejection. These studies will develop preclinical rationale and strategies for using genetically modified dendritic cells for immunization to defined cancer antigens.