Project 3

临床前和临床研究表明，光动力疗法(PDT)可以增强宿主的免疫反应。我们的新发现是，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，无论是体内还是体外，PDT治疗肿瘤细胞都能增强它们被宿主免疫系统识别的能力。我们已经证明，增强肿瘤的免疫原性可以与成熟和激活抗原提呈细胞的能力相关，我们假设Photofrin-PDT刺激免疫介质的表达，从而能够增加抗原提呈细胞的活性。在这项建议的具体目标I中，我们将确定光诱导光动力疗法产生的肿瘤细胞裂解物中存在的激活树突状细胞的因子(S)。我们进一步假设免疫增强因子的分泌依赖于 肿瘤的初始免疫原性和所采用的PDT方案的类型。这一假设将在特定目标II中得到验证。在特定目标III中，我们将测试临床光动力疗法是否像临床前光动力疗法一样，增强抗肿瘤免疫反应。这个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了解。对这些机制的理解将潜在地允许开发一种最佳的“免疫增强”PDT方案，这可能提供一种提高患者对抗肿瘤和/或 治疗范围外的转移。

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.