Project 3

临床前和临床研究表明，光动力疗法（PDT）增强了宿主的免疫反应。 我们已经取得了新的发现，即Photofrin-PDT对肿瘤细胞的直接作用足以刺激宿主免疫系统。该项目的总体目标是了解PDT如何在体内和体外增强肿瘤细胞的免疫原性。我们假设肿瘤细胞的PDT治疗，在体内或体外增强其被宿主免疫系统识别的能力。我们已经表明，增加的肿瘤免疫原性可以与成熟和激活抗原呈递细胞的能力相关，我们假设Photofrin-PDT刺激能够增加抗原呈递细胞活性的免疫介质的表达。在本提案的具体目标I中，我们将鉴定Photofrin-PDT产生的肿瘤细胞裂解物中存在的激活树突状细胞的因子。我们进一步假设，免疫增强因子的分泌依赖于细胞的免疫功能。 肿瘤的初始免疫原性和所用PDT方案的类型。这一假设将在《具体目标II》中得到检验。在Specific Aim III中，我们将测试临床PDT是否像临床前PDT一样增强抗肿瘤免疫应答。本项目中概述的研究将进一步加深我们对PDT如何影响宿主免疫反应的认识。对这些机制的理解将潜在地允许开发最佳的“免疫增强”PDT方案，其可以提供改善患者对抗肿瘤和/或免疫缺陷的能力的手段。 治疗野外的转移。

Preclinical and clinical studies have shown that Photodynamic Therapy (PDT) augments the host immune response. We have made that novel discovery that the direct effects of Photofrin-PDT on tumor cells are sufficient to stimulate the host immune system. The overall goal of this project is understand how PDT enhances the immunogenicity of tumor cells, in vivo and in vitro. We hypothesize the PDT treatment of tumor cells, in vivo or in vitro enhances their ability to be recognized by the host immune system. We have shown that increased tumor immunogenicity can be correlated with an ability to mature and activate antigen-presenting cells and we hypothesize that Photofrin-PDT stimulates the expression of immune mediators that are able to increase the activity of antigen-presenting cells. In Specific Aim I of this proposal we will identify the factor(s) present in Photofrin-PDT generated tumor cell lysates that activate dendritic cells. We further hypothesize that the secretion of immune enhancing factors is dependent upon the initial immunogenicity of the tumor and the type of PDT regimen employed. This hypothesis will be tested in Specific Aim II. In Specific Aim III we will test whether clinical PDT, like preclinical PDT, augments the anti-tumor immune response. The studies outlined in this project will further our knowledge of how PDT affects the host immune response. An understanding of these mechanisms will potentially allow for the development of an optimal "immune enhancing" PDT protocol, which may provide a means of improving the patients ability to combat tumor and/or metastases outside the treatment field.