Project 3: Immune Response to PDT

尽管有积极的治疗，但转移性或晚期头颈部肿瘤患者的治愈率 鳞状细胞癌（HNSCC）低于50%，复发率范围为25- 50%，取决于 疾病现场。目前治疗方式的毒性经常阻碍治疗升级， 挽救治疗导致显著的发病率，而对结果的影响最小。因此，新治疗 因此，需要新的治疗策略，并且对HNSCC的免疫治疗重新产生了兴趣。光动力疗法 (PDT)诱导急性局部和全身炎症，导致增强的抗肿瘤免疫力， 控制远距离疾病的潜力。该项目的总体假设是PDT诱导急性 炎症逆转肿瘤介导的免疫抑制并刺激抗肿瘤免疫。的能力 PDT和PDT产生的疫苗增强免疫细胞活化和HNSCC肿瘤细胞的识别 将进行检查，目的是通过激活免疫系统来预防或减少HNSCC复发。 这将大大促进这种疾病的治疗。这个项目的重点是了解 PDT增强抗肿瘤免疫的机制，长期目标是扩大PDT的使用， PDT作为增强抗肿瘤免疫的佐剂。为了实现这一目标， 1）HNSCC的PDT诱导急性炎症，导致抗肿瘤活性增加， 效应细胞和调节性T细胞的减少，导致抗肿瘤免疫力增加; 2）激活 PDT诱导的Th 17细胞导致IL 17分泌增强，IL 17与IL 1协同作用诱导中性粒细胞 介导TDLN内DC活化的增强，导致抗肿瘤CD 8 + T细胞的刺激; 和3）PDT产生的HNSCC肿瘤细胞裂解物可以安全地用于增强HNSCC患者的抗肿瘤免疫力。 HNSCC患者。该项目中提出的研究是令人信服的，因为它们有可能 证明HNSCC的PDT能够克服肿瘤诱导的免疫抑制并激活抗- 肿瘤免疫;从而为扩大PDT的应用提供了合理的理由，超越了其目前作为局部免疫的用途。 疗法这些研究对本项目资助（PPG）的目标至关重要，因为它们将提供 关于患者的免疫状态对HNSCC中PDT功效的影响的重要信息，进一步 将PDT从利基疗法转变为HNSCC的标准治疗的总体目标， 了解PDT的机制和患者免疫状态在PDT疗效中的作用。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进该领域， 患者，扩大了对PDT诱导的急性炎症在抗肿瘤免疫中的作用的理解 和长期肿瘤生长控制，并开始评估PDT产生的抗肿瘤 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.