Immunotherapy for Skin Cancer Precursors to Prevent Skin Cancer

项目摘要/摘要： 最近利用患者自身免疫细胞对抗转移性癌症的成功凸显了免疫细胞的能力 免疫系统为黑色素瘤等晚期癌症患者提供持续缓解。然而， 免疫系统在消除癌前细胞并防止其进展为侵袭性细胞方面的作用 癌症仍然不确定。确定激活免疫系统预防癌症的益处 发展和复发，我们研究导致有效免疫激活的免疫途径 皮肤癌发展的早期阶段。非黑色素瘤皮肤癌 (NMSC) 是最常见的 美国常见的癌症诊断。皮肤鳞状细胞癌（SCC）与 患有严重的疾病，包括毁容、溃疡和感染，死亡率与 黑色素瘤。重要的是，鳞状细胞癌前兆可以在临床上识别和治疗。基于令人信服的 根据临床前数据，我们进行了一项随机双盲临床试验，其中我们发现外用卡泊三醇 与 5-氟尿嘧啶 (5-FU) 一起促进针对皮肤癌的强大适应性免疫激活 前体、光化性角化病及其完全清除。重要的是，这种免疫疗法导致 试验后 3 年，与 5-FU 单药治疗组相比，SCC 风险显着降低。为了确定 卡泊三醇加 5-FU 对皮肤早期癌前细胞作用的精确机制，并充分 利用其预防皮肤癌的潜力，我们的目标是 (1) 确定引导免疫细胞的信号 用卡泊三醇加 5-FU 组合处理癌前细胞，（2）研究其机制 这些激活的免疫细胞消除目标肿瘤细胞，并且（3）识别免疫细胞和因子 介导卡泊三醇加 5-FU 对 SCC 的长期保护作用。的结果 拟议的研究将确定免疫激活在对抗皮肤早期阶段的基本作用 癌症的发展，并为使用卡泊三醇加 5-FU 组合治疗皮肤癌提供理论依据 免疫治疗和免疫预防。

Project Summary/Abstract: Recent success in utilizing patients’ own immune cells to combat metastatic cancers highlights the ability of the immune system in providing sustained remission for patients with late-stage cancers like melanoma. However, the role of the immune system in eliminating premalignant cells and preventing their progression to invasive cancers remains uncertain. To determine the benefit of activating the immune system to prevent cancer development and recurrence, we study the immune pathways that lead to effective immune activation against early phases of skin cancer development. Non-melanoma Skin cancers (NMSCs) are collectively the most commonly diagnosed cancers in the United States. cutaneous squamous cell carcinoma (SCC) is associated with severe morbidities including disfigurement, ulceration and infection, and a mortality rate similar to that of melanoma. Importantly, the SCC precursors can be clinically identified and treated. Based on compelling preclinical data, we have performed a randomized double-blind clinical trial in which we find topical calcipotriol together with 5-fluorouracil (5-FU) to promote a robust adaptive immune activation against skin cancer precursors, actinic keratoses, and their complete clearance. Importantly, this immunotherapy led to a significantly lower risk of SCC compared to 5-FU monotherapy group in 3 years post-trial. In order to determine the precise mechanism of calcipotriol plus 5-FU action against early premalignant cells in the skin, and to fully harness its potential to prevent skin cancer, we aim to (1) determine the signals that direct the immune cells to the premalignant cells treated with calcipotriol plus 5-FU combination, (2) investigate the mechanism by which these activated immune cells eliminate the targeted tumor cells, and (3) identify the immune cells and factors that mediate the long-term protective effects of calcipotriol plus 5-FU against SCC. The outcomes of the proposed research will establish a fundamental role for immune activation in combating the early stages of skin cancer development and provide the rationale for the use of calcipotriol plus 5-FU combination in skin cancer immunotherapy and immunoprevention.