Photodynamic Therapy (PDT) Mechanisms: Tumor Immunity

描述（由申请人提供）：临床前和临床研究表明，光动力疗法（PDT）通过未知机制增强宿主免疫反应。以前的研究，主要是描述性的，已经表明：1）肿瘤对PDT的反应是由一个完整的免疫系统增强; 2）PDT促进免疫记忆细胞的形成; 3）PDT增强肿瘤免疫是由T细胞介导的。我们已经做出了新的发现，即Photofrin（Pf）-PDT对肿瘤细胞的直接作用足以刺激宿主抗肿瘤应答，并且刺激抗肿瘤应答的能力可以与抗原呈递细胞（APC）的活化相关。我们还表明，PDT对肿瘤免疫原性的改变取决于固有的肿瘤免疫原性和所采用的PDT方案。这些数据导致了这样的假设，即PDT治疗导致能够激活APC的免疫介质的表达，所述APC刺激肿瘤特异性T细胞并触发细胞介导的抗肿瘤免疫应答的起始。我们进一步假设激活APC的能力取决于光敏剂、所采用的PDT方案和肿瘤的免疫原性。该提案的总体目标是了解PDT如何增强肿瘤细胞免疫原性以及导致宿主免疫应答增强的机制。在第一部分，我们将研究HSP和炎性细胞因子在PDT增强肿瘤免疫原性中的作用。在具体目标II中，我们将研究PDT对体内宿主免疫应答激活的直接和次要作用的作用，作为PDT方案的功能，并将研究增强的免疫应答对抗远处疾病的能力。在Specific Aim III中，我们将使用转基因小鼠模型和四聚体和ELISPOT分析来确定已响应于PDT而被激活的肿瘤特异性T细胞的动力学和特征。最后，在具体目标IV中，我们将扩展我们的原始发现，即Photofrin-PDT产生的肿瘤细胞裂解物是有效的抗癌疫苗，通过确定PDT疫苗是否能够增强宿主对已建立肿瘤的免疫反应，从而促进肿瘤控制。本提案中概述的研究主要是机制性的，并将为设计具有最佳免疫增强能力的PDT方案指明方向，这可能导致增强治疗领域内外的肿瘤长期控制。

DESCRIPTION (provided by applicant): Preclinical and clinical studies have shown that Photodynamic Therapy (PDT) augments the host immune response by unknown mechanisms. Previous studies, which have largely been descriptive, have shown that 1) the tumor response to PDT is augmented by an intact immune system; 2) PDT promotes the formation of immune memory cells; 3) PDT enhanced tumor immunity is mediated by T cells. We have made the novel discovery that the direct effects of Photofrin (Pf)-PDT on tumor cells is sufficient to stimulate the host anti-tumor response and that the ability to stimulate an antitumor response can be correlated to activation of antigen-presenting cells (APCs). We have also shown that alterations in tumor immunogenicity by PDT are dependent upon the inherent tumor immunogenicity and the PDT protocol employed. These data have led to the hypothesis that PDT treatment results in the expression of immune mediators that are able to activate APCs, which stimulate tumor specific T cells and trigger the initiation of a cell-mediated antitumor immune response. We further hypothesize that the ability to activate APCs is dependent upon the photosensitizer, the PDT protocol employed and the immunogenicity of the tumor. The overall goal of this proposal is to understand how PDT enhances tumor cell immunogenicity and the mechanisms that lead to the augmentation of the host immune response. In Specific Aim I we will examine the role of HSP and inflammatory cytokines in the ability of PDT to enhance tumor immunogenicity. In Specific Aim II we will examine the role of direct and secondary effects of PDT on the activation of the host immune response in vivo as a function of PDT protocol and will examine the ability of the enhanced immune response to combat distant disease. In Specific Aim III we will use transgenic mouse models and tetramer and ELISPOT analyses to determine the kinetics and characteristics of tumor specific T cells that have been activated in response to PDT. Finally, in Specific Aim IV we will expand upon our original findings that Photofrin-PDT-generated tumor cell lysates are effective anti-cancer vaccines by determining whether PDT vaccines are able to augment the host immune response against established tumors and thus promote tumor control. The studies outlined in this proposal are primarily mechanistic and will point the way toward the design of PDT protocols with optimal immune enhancing capabilities, which could lead to enhancement of long-term control of tumors within and outside the treatment field.