Photodynamic Therapy (PDT) Mechanisms: Tumor Immunity

描述(申请人提供)：临床前和临床研究表明，光动力疗法(PDT)通过未知的机制增强宿主的免疫反应。以前的研究大多是描述性的，表明1)完整的免疫系统增强了肿瘤对PDT的反应；2)PDT促进了免疫记忆细胞的形成；3)PDT增强了肿瘤免疫是由T细胞介导的。我们的新发现是，Photofrin(PF)-PDT对肿瘤细胞的直接作用足以刺激宿主的抗肿瘤反应，并且刺激抗肿瘤反应的能力可以与抗原提呈细胞(APC)的激活相关。我们还表明，PDT对肿瘤免疫原性的改变依赖于固有的肿瘤免疫原性和所采用的PDT方案。这些数据导致了一种假设，即PDT治疗导致免疫介质的表达，这些免疫介质能够激活APC，从而刺激肿瘤特异性T细胞并触发细胞介导的抗肿瘤免疫反应。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。这项建议的总体目标是了解PDT如何增强肿瘤细胞的免疫原性，以及导致宿主免疫反应增强的机制。在特定目的I中，我们将研究热休克蛋白和炎性细胞因子在光动力疗法增强肿瘤免疫原性能力中的作用。在特定的目标II中，我们将研究PDT对体内宿主免疫反应激活的直接和继发性作用作为PDT方案的功能，并将检查增强的免疫反应对抗远距离疾病的能力。在特殊目的III中，我们将使用转基因小鼠模型以及四聚体和ELISPOT分析来确定肿瘤特异性T细胞在PDT反应中被激活的动力学和特征。最后，在特定的目标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的肿瘤的免疫反应，从而促进肿瘤控制。该提案中概述的研究主要是机械性的，将为设计具有最佳免疫增强能力的PDT方案指明方向，这可能导致加强对治疗领域内外肿瘤的长期控制。

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.