Early investigation of the role of desmoplastic fibrosis in cutaneous squamous cell carcinoma

项目总结/摘要 FDA批准的唯一一种治疗晚期皮肤鳞状细胞癌（CSCC）的药物（cemiplimab， 免疫治疗药物，帮助免疫系统杀死癌细胞）只对50%的患者有效。那里 没有已知的CSCC免疫治疗失败的预测因子。解决这一知识差距， 免疫治疗往往失败是我们能够进一步降低发病率和死亡率的核心， CSCC和免疫疗法发挥主要作用的其他癌症。结缔组织增生（异常结缔组织沉积） 胶原蛋白）是CSCC的独立预后因素， 死亡然而，量化结缔组织增生的系统尚未开发，以及它如何引起不良反应。 尚未研究CSCC的结局。我们的实验室试图确定为什么结缔组织增生与 可怜的结果。我们已经开发了第一个定量结缔组织增生的系统。我们的早期数据表明 突出的结缔组织增生与明显较低的5年治愈率（60%）相关， 无结缔组织增生（90%）。我们的数据还表明，当免疫细胞不浸润肿瘤时， 更糟（40%对75%，当免疫T细胞存在时）。最后，我们注意到， 结缔组织增生是一种免疫细胞被结缔组织增生性结缔组织隔离远离肿瘤的模式。 地区如果这是真的，结缔组织增生可能是免疫治疗失败的主要机制， 如果T细胞不与肿瘤细胞接触，这种疗法就不能起作用。我们建议证实结缔组织增生是 与转移和死亡以及T细胞与肿瘤接触减少相关的基因，并鉴定 可能参与促结缔组织增生/纤维化途径和T细胞排斥。如果拟议的研究表明， 结缔组织增生与T细胞从肿瘤中排除有关，进一步的研究旨在对抗结缔组织增生， 提高免疫治疗的效果。

Project Summary/Abstract The only FDA-approved treatment for advanced cutaneous squamous cell carcinoma (CSCC) (cemiplimab, an immunotherapy drug that helps the immune system kill cancer cells) is only effective in 50% of patients. There are no known predictors of immunotherapy failure in CSCC. Addressing this gap in knowledge regarding why immunotherapy often fails is central to our ability to further decrease morbidity and mortality from CSCC and other cancers in which immunotherapy plays a major role. Desmoplasia (deposition of abnormal collagen in the area around a tumor) is an independent prognostic factor in CSCC associated with death. However, systems for quantifying desmoplasia have not been developed and how it causes poor outcomes in CSCC has not been studied. Our laboratory seeks to determine why desmoplasia is linked to poor outcomes. We have developed the first system for quantifying desmoplasia. Our early data indicate prominent desmoplasia is associated with a markedly lower 5-year cure rate (60%) as compared to when there is no desmoplasia (90%). Our data also indicate that when immune cells do not infiltrate tumors, cure rate is worse (40% vs. 75% when immune T cells are present). Finally, we have noted in cases of prominent desmoplasia a pattern whereby immune cells are sequestered away from the tumor by the desmoplastic region. If this is true, desmoplasia may be a major mechanism accounting for failure of immunotherapy since this therapy cannot work without T cell contact with tumor cells. We propose to verify that desmoplasia is associated with metastasis and death as well as decreased T cell contact with tumor, and to identify genes that may be involved in the desmoplastic/fibrotic pathway and T cell exclusion. If the proposed studies show that desmoplasia is linked to T cell exclusion from tumor, further studies aimed at combatting desmoplasia may be enable greater efficacy of immunotherapy.