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.

项目摘要/摘要 FDA批准的唯一治疗晚期皮肤鳞状细胞癌(CSCC)的药物 帮助免疫系统杀死癌细胞的免疫疗法药物)只对50%的患者有效。那里 都不是CSCC免疫治疗失败的已知预测因素。解决有关原因的认识上的差距 免疫疗法经常失败是我们进一步降低发病率和死亡率的核心 鳞状细胞癌和其他免疫治疗起主要作用的癌症。促结缔组织增生症(异常沉积 肿瘤周围区域的胶原蛋白)是CSCC的独立预后因素 死亡。然而，还没有开发出量化促结缔组织发育的系统，以及它是如何导致不良的。 CSCC的结局还没有研究过。我们的实验室试图确定为什么促结缔组织增生症与 糟糕的结果。我们已经开发了第一个用于量化促结缔组织发育的系统。我们早期的数据显示 显著的促结缔组织增生症与较低的5年治愈率(60%)有关。 无结缔组织增生症(90%)。我们的数据还表明，当免疫细胞没有渗入肿瘤时，治愈率是 更糟糕的是(40%，而免疫T细胞存在时为75%)。最后，我们注意到在突出的情况下 促结缔组织增生症：免疫细胞通过促结缔组织增生与肿瘤隔离的一种模式。 区域。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，因为 如果T细胞不与肿瘤细胞接触，这种疗法就不能奏效。我们建议验证促结缔组织增生症 与转移和死亡以及T细胞与肿瘤接触减少有关，并识别与 可能参与了促结缔组织增生/纤维化途径和T细胞排斥反应。如果拟议的研究表明 促结缔组织增生与肿瘤外T细胞排斥有关，旨在对抗促结缔组织增生症的进一步研究可能 使免疫疗法发挥更大的疗效。