Immunotherapy for Skin Cancer Precursors to Prevent Skin Cancer

项目摘要/摘要： 最近利用患者自身的免疫细胞对抗转移性癌症的成功突显了 免疫系统在为黑色素瘤等晚期癌症患者提供持续缓解方面的作用。然而， 免疫系统在清除癌前细胞和防止其向侵袭性发展中的作用 巨蟹座仍然不确定。确定激活免疫系统预防癌症的益处 发展和复发，我们研究了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(NMSCs)是最常见的 在美国被普遍诊断为癌症。皮肤鳞状细胞癌与 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，鳞状细胞癌的前体可以在临床上识别和治疗。基于令人信服的 临床前数据，我们进行了一项随机双盲临床试验，在该试验中，我们发现外用钙泊三醇 联合5-氟尿嘧啶(5-FU)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，以及它们的完全清除。重要的是，这种免疫疗法导致了 在试验后3年，与5-FU单一治疗组相比，SCC的风险显著降低。为了确定 钙泊三醇联合5-FU对皮肤早期癌前细胞的确切作用机制 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 钙泊三醇联合5-FU治疗癌前病变细胞，(2)探讨其作用机制。 这些被激活的免疫细胞清除目标肿瘤细胞，以及(3)识别免疫细胞和因子 这可能是钙泊三醇联合5-FU对鳞癌的长期保护作用。这次会议的结果 拟议中的研究将确立免疫激活在对抗皮肤早期阶段中的基础作用 肿瘤的发生，并为使用钙泊三醇联合5-FU治疗皮肤癌提供了理论依据 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.