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

项目总结/文摘

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.