Project 3: Immune Response to PDT

尽管进行了积极的治疗，但转移性或晚期头颈部患者的治愈率 鳞状细胞癌(HNSCC)低于50%，复发率从25%到50%不等，具体取决于 疾病现场。目前治疗方式的毒性经常阻止治疗升级和 抢救治疗会导致显著的发病率，对预后的影响很小。因此，新的治疗方法 策略是需要的，人们对免疫治疗HNSCC重新产生了兴趣。光动力疗法 光动力疗法(PDT)诱导急性局部和全身炎症，导致抗肿瘤免疫增强，这对 有可能控制遥远的疾病。这个项目的总体假设是，光动力疗法诱导急性 炎症逆转肿瘤介导的免疫抑制，刺激抗肿瘤免疫。的能力 PDT和PDT疫苗增强免疫细胞活化和对HNSCC肿瘤细胞的识别 将进行检查，目的是通过激活免疫来预防或减少HNSCC复发 系统，这将大大推进这种疾病的治疗。本项目的重点是了解 PDT增强抗肿瘤免疫的机制及扩大其应用的远期目标 光动力疗法作为增强抗肿瘤免疫的佐剂。要实现这一目标，需要采取以下措施 假说将得到检验1)HNSCC的PDT诱导急性炎症，导致抗肿瘤作用增强 效应细胞和调节性T细胞的减少导致抗肿瘤免疫增强；2)激活 PDT诱导Th17细胞分泌IL-17，与IL-1协同诱生中性粒细胞 介导增强TDLN内DC的激活，从而刺激抗肿瘤的CD8+T细胞； PDT产生的HNSCC肿瘤细胞裂解物可安全地用于增强小鼠的抗肿瘤免疫 HNSCC患者。这个项目中提出的研究是令人信服的，因为它们有可能 提示HNSCC的光动力疗法能够克服肿瘤诱导的免疫抑制，激活抗肿瘤免疫。 肿瘤免疫；从而为将PDT的应用范围扩大到目前的局部应用提供了理性 心理治疗。这些研究对本计划项目赠款(PPG)的目标至关重要，因为它们将提供 关于患者免疫状态对HNSCC PDT疗效影响的重要信息，进一步 将PDT从一种利基疗法转变为HNSCC的标准护理的总体目标是 了解光动力疗法的机制以及患者的免疫状态在光动力疗法疗效中所起的作用。这 该项目将通过确定PDT对肿瘤诱导的免疫抑制的影响来推动这一领域的发展 患者，扩大了对PDT诱导的急性炎症在抗肿瘤免疫中作用的认识 并长期控制肿瘤生长并开始评估PDT产生的抗肿瘤的潜力 疫苗。

Despite aggressive treatment, the cure rate for patients with metastatic or advanced stage head and neck squamous cell carcinoma (HNSCC) is below 50% with recurrence rates ranging from 25-50%, depending on the disease site. Toxicity of the current treatment modalities frequently prevents treatment escalation and salvage therapies result in significant morbidity with minimal effect on outcome. Therefore novel treatment strategies are needed and there is renewed interest in immunotherapy for HNSCC. Photodynamic therapy (PDT) induces acute local and systemic inflammation that leads to enhanced anti-tumor immunity, which has potential to control distant disease. The overall hypothesis of this project is that PDT induction of acute inflammation reverses tumor-mediated immunosuppression and stimulates anti-tumor immunity. The ability of PDT and PDT-generated vaccines to enhance immune cell activation and recognition of HNSCC tumor cells will be examined with the intent of preventing or reducing HNSCC recurrence through activation of the immune system, which would significantly advance treatment of this disease. The focus of this project is to understand the mechanisms of PDT-enhancement of anti-tumor immunity with the long-term goal of expanding the use of PDT as an adjuvant for augmentation of anti-tumor immunity. To accomplish this goal the following hypotheses will be tested 1) PDT of HNSCC induces acute inflammation leading to increases in anti-tumor effector cells and decreases in regulatory T cells resulting in increased anti-tumor immunity; 2) activation of Th17 cells by PDT leads to enhanced secretion of IL17 that works in collaboration with IL1 to induce neutrophil mediated enhancement of DC activation within the TDLN resulting in stimulation of anti-tumor CD8+ T cells; and 3) PDT generated HNSCC tumor cell lysates can be used safely to augment anti-tumor immunity in HNSCC patients. The studies proposed in this project are compelling in that they have the potential to demonstrate that PDT of HNSCC is able to overcome tumor induced immunosuppression and activate anti- tumor immunity; thus providing rational for expanding the application of PDT beyond its current use as a local therapy. These studies are critical to the goals of this program project grant (PPG), as they will provide important information on the effect of the immune status of the patient on PDT efficacy in HNSCC, furthering the overall goal of moving PDT from a niche therapy to a standard of care for HNSCC though a deeper understanding of the mechanisms of PDT and the role the patient immune status plays in PDT efficacy. This Project will advance the field by determining the effect of PDT on tumor induced immunosuppression in patients, expanding the understanding of the role of PDT induced acute inflammation in anti-tumor immunity and long-term tumor growth control and beginning to assess the potential of PDT-generated anti-tumor vaccines.