Abstract
273 Background: Cholangiocarcinoma (CC) is a highly lethal malignancy with a poor 5 year overall survival in the advanced setting. Benefits of treating CC with chemotherapy are limited and no FDA approved targeted therapies currently exist. CC is associated with a desmoplastic reaction comprised of extracellular matrix, fibroblasts and inflammatory leukocytes. Myeloid-derived suppressor cells (MDSC) are the predominant tumor infiltrating leukocytes in several cancers, but little is known about their role in CC. MDSCs are derived from a monocytic (M-MDSC) or granulocytic (G-MDSC) origin and infiltrate the tumor microenvironment (TME) where they suppress anti-tumor immunity and play a crucial role in tumor growth, chemoresistance and metastasis. Here, we characterize the prevalence and prognostic significance of MDSC in CC. Methods: A de-identified human CC clinical database (n = 220) with linked tumor tissue was collected under an IRB approved protocol. Total white blood cell count and percent monocytes (a surrogate marker for M-MDSC prevalence in peripheral circulation) before starting therapy were collected and correlated with overall survival in patients with unresectable CC. Immunohistochemistry for myeloid cell markers (CD33, CD11b, CD14, CCR2, and CD15) was performed on formalin-fixed paraffin embedded human CC and normal liver sections. Staining was scored by a pathologist or quantified with digital imaging software. Results: Analysis of chemotherapy naive blood specimens revealed that an increase in monocyte percentage inversely correlated with survival in patients with unresectable CC (p = 0.0117). Statistical significance was more pronounced in patients with intrahepatic CC (p = 0.0091) compared to other disease sites. There was an increased level of M-MDSC and G-MDSC in CC compared to normal liver tissue and all 22 tested CC samples stained positively for MDSC markers within the tumor stroma. Conclusions: The prevalence of circulating monocytes correlates negatively with prognosis and MDSCs infiltrate the TME in unresectable CC. Therefore, targeting MDSC is an attractive therapeutic strategy and future studies aim to fully characterize the TME and block MDSC recruitment in a mouse model of CC.
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