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

促结缔组织增生性纤维化在皮肤鳞状细胞癌中作用的早期研究

• 批准号: 10202093
• 负责人: Chrysalyne Delling Schmults
• 金额: $ 8.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-04 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202093
• 关键词: Accounting; Address; Age; American Joint Committee on Cancer; Area; Band Cell; Biochemical; Bioinformatics; Biological; Blood Vessels; Cell Communication; Cells; Cessation of life; Clinical; Collagen; Community Clinical Oncology Program; Data; Death Rate; Deposition; Desmoplastic; Disease; Exclusion; Expression Profiling; FDA approved; Failure; Fibrosis; Gender; Gene Expression; Gene Expression Profiling; Genes; Histologic; Image; Immune; Immune system; Immunofluorescence Immunologic; Immunohistochemistry; Immunooncology; Immunotherapy; Impotence; Infiltration; Investigation; Knowledge; Laboratories; Link; Lymphatic; Lymphocyte; Lymphovascular; Malignant Neoplasms; Measures; Mediating; Modeling; Morbidity - disease rate; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Play; Population; Prognostic Factor; Proteins; Recurrence; Research; Research Personnel; Resistance; Risk; Role; Slide; Structure; System; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissue Microarray; Tissue Sample; Tissue-Specific Gene Expression; Tumor Escape; Tumor stage; Tumor-infiltrating immune cells; Work; anti-PD-1; cancer cell; cytotoxic; innovation; insight; interest; lymphatic vessel; mRNA Expression; melanoma; mortality; nano-string; neoplastic cell; novel; prevent; protein expression; response; skin squamous cell carcinoma; tumor

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.

项目概要/摘要 FDA 唯一批准的治疗晚期皮肤鳞状细胞癌 (CSCC) 的药物（cemiplimab，一种 帮助免疫系统杀死癌细胞的免疫治疗药物）仅对 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。解决关于原因的知识差距 免疫疗法经常失败对于我们进一步降低发病率和死亡率的能力至关重要 免疫治疗在 CSCC 和其他癌症中发挥着重要作用。结缔组织增生（异常沉积 肿瘤周围区域的胶原蛋白）是与以下疾病相关的 CSCC 的独立预后因素 死亡。然而，尚未开发出量化结缔组织形成及其如何导致不良后果的系统。 尚未研究 CSCC 的结果。我们的实验室试图确定为什么结缔组织增生与 结果不佳。我们开发了第一个量化结缔组织增生的系统。我们的早期数据表明 与有结缔组织增生的情况相比，明显结缔组织增生的 5 年治愈率 (60%) 显着降低 没有结缔组织增生（90%）。我们的数据还表明，当免疫细胞不浸润肿瘤时，治愈率是 更糟（当免疫 T 细胞存在时，为 40% vs. 75%）。最后，我们注意到一些突出的案例 促纤维增生是一种免疫细胞通过促纤维增生而远离肿瘤的模式 地区。如果这是真的，结缔组织增生可能是免疫治疗失败的一个主要机制，因为 如果 T 细胞不与肿瘤细胞接触，这种疗法就无法发挥作用。我们建议验证结缔组织增生是 与转移和死亡以及 T 细胞与肿瘤接触减少相关，并鉴定基因 可能参与促纤维增生/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，旨在对抗结缔组织增生的进一步研究可能是 使免疫疗法发挥更大功效。