Immunotherapy for Skin Cancer Precursors to Prevent Skin Cancer

项目概要/摘要： 最近在利用患者自身免疫细胞对抗转移性癌症方面的成功突出了免疫系统的能力。 免疫系统为晚期癌症患者（如黑色素瘤）提供持续缓解。然而，在这方面， 免疫系统在消除癌前细胞和防止其进展为侵袭性细胞中的作用 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 在美国常见的癌症。皮肤鳞状细胞癌（SCC）与 有严重的发病率，包括毁容，溃疡和感染，死亡率与 黑素瘤重要的是，SCC前体可以在临床上识别和治疗。基于引人注目的 临床前数据，我们进行了随机双盲临床试验，我们发现局部卡泊三醇 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，这种免疫疗法导致了 试验后3年，与5-FU单药治疗组相比，SCC风险显著降低。为了确定 卡泊三醇加5-FU对皮肤早期癌前细胞作用的确切机制， 利用其预防皮肤癌的潜力，我们的目标是（1）确定指导免疫细胞的信号， 卡泊三醇联合5-FU处理癌前病变细胞，（2）研究其作用机制， 这些活化的免疫细胞消除靶向肿瘤细胞，和（3）鉴定免疫细胞和因子 介导卡泊三醇加5-FU对SCC的长期保护作用。的成果 拟议中的研究将确立免疫激活在对抗皮肤病早期阶段中的基本作用。 癌症的发展，并提供了在皮肤癌中使用卡泊三醇加5-FU组合的基本原理 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.