Abstract A34: Characterizing macrophage adaptive function in tumor stroma
Authors: Hostetter Galen , Sinha Arkadeep , Haab Brian 
Published: May 2015

Tumor associated macrophages (TAMs) are considered a critical component of the desmoplastic response, a variable host-tumor response and an ongoing research focus. Research and experimental plans have increased in complexity to better characterize the interactions and biological roles of the components of desmoplasia as a ‘response or a niche’. Histopathology markers of tumor microinvasion and frank invasion via basement membrane (collagen IV) highlight loss of specific staining (Vimentin). More recently, evidence of direct communication / protein gradients between tumor and stromal cells can direct and predict metastasis to include subsets of mesenchymal derived cells even before standard methods of tumor detection. Here we examine the macrophage components that contribute to this process in parallel with the invasive phenotype of collagen turnover in fibroblasts and macrophages.

Early work at our institution identified gene expression changes caused by TGF-β; induced EMT in pancreatic cancer cell lines and were validated on tissue microarrays (TMA). The tissue based studies highlighted the significant role of the TME components of macrophages (stained CD68), cancer associated fibroblasts related to hypoxia (Hif 1α) and developmental marker (Sonic Hedgehog). Here we validate Mannose receptor C-type 2 (MRC2), found to be one of the top changes from the expression profiling data. MRC2 is normally present on certain fibroblasts and macrophages and involved in the matrix reorganization process with specific domains for binding glycosylated ligands and leading to altered glycosylation. MRC2 expression has been analyzed by immunohistochemistry (IHC) on 179 Whipple resections for suspected pancreatic adenocarcinomas (PDAC) with distributions of staining intensity 0 to 4 calculated for normal (including chronic pancreatitis), PDAC and metastatic PDAC [0.7, 1.0 and 1.1) Secondly, we performed an IHC study to better determine functional expression and the role of MRC2 in the stromal macrophage populations of M1 macrophages stained for CD68 and as M2 macrophages for CD163. These antibodies are commercially available and will be used to evaluate the tumor surveillance / immunity function of M1 macrophages and / or the tumor suppressive function of M2 macrophages. Single and dual labeled IHC strategies will be utilized to highlight the macrophage context of observed variation in MRC2 intensity. Increased stromal MRC2 staining intensity is associated with poor prognosis; however, significant variation is noted in the pancreatic tumor tissues. In addition, though patients with diagnosis of chronic pancreatitis are generally much lower in expression, several tissues showed marked staining and could portend a worst prognosis.

Citation Format: Galen Hostetter, Arkadeep Sinha, Brian Haab. Characterizing macrophage adaptive function in tumor stroma. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A34. doi:10.1158/1538-7445.CHTME14-A34