The tumor microenvironment in cholangiocarcinoma: Impact of natural killer cells on overall survival.

Abstract

e16331 Background: Cholangiocarcinoma (CCA) describes a malignancy originating from the epithelial cells of the bile ducts. While rare, this malignancy often has an unfortunate outlook given its advanced stage at presentation. Development of CCA likely depends upon a gradual accumulation of genetic mutations. These mutations in-turn, transition precursor lesions, biliary intraepithelial neoplasia and intraductal papillary mucinous neoplasm, into the cancer that is CCA. The tumor microenvironment has been increasingly studied and likely plays a big role in the pathogenesis of CCA. A variety of cells contribute to said environment, ranging from regulatory T cells(Treg) to natural killer(NK) cells. The role of the NK cell is being increasingly studied in the context of CCA as it is one of the most abundant immune cells in the tumor microenvironment and likely plays a large role in the immune response to cancer cells. Methods: Our sample set included 36 patients from a publicly available RNA sequencing dataset from MD Anderson. RNA sequences were extracted and then input into a Stanford based application, CIBERSORT. This illustrates the impact different immune cells have on a tumor microenvironment. The immune cells included are the following: B-cells naïve, B-cells memory, plasma cells, CD8 T-cells, CD4 T-cells, T-cells follicular, T-cells regulatory, natural killer activated cells, natural killer resting cells, monocytes, macrophages (M0, M1, M2), activated dendritic cells, resting dendritic cells, activated mast cells, resting mast cells, eosinophils, and neutrophils. CIBERSORT uses immune cell fractions as the marker of immune cell impact. These fractions were then analyzed in a statistical tool, Radiant by Shiny, that computes a linear regression describing the relationship between immune cells and impact on overall survival. Results: Natural killer cells in the tumor microenvironment have a strong, positive impact on overall survival (p = 0.044). The coefficient of correlation was +198. Conclusions: Results of our analysis illustrate the strong and positive relationship that NK cells have on the overall survival of CCA. This is likely due to the NK cell’s ability to promote cell death through various pathways, such as the Fas-L and TNF apoptotic pathways. More specifically, it has been shown that cholangiocytes may have the ability to present lipid antigens to NK cells thus activating an alternate killing pathway making the NK cell a crucial player in the tumor microenvironment. This, coupled with being one of the most abundant cells in the tumor microenvironment in CCA, opens the door for the NK cell as an potential target for future treatment options. Understanding these specific interactions between NK cells and tumor cells proves to be essential for developing novel therapeutic strategies.