Abstract P3-05-14: Recognition of glycan-epitopes by the macrophage glycoreceptor CLEC10A is associated with improved outcome in primary breast cancer (2013)

Abstract Background: Glycosylation of proteins and lipids is a frequent posttranslational modification involved in the regulation of many important biological processes such as cell proliferation, cell adhesion, cell migration, protein turnover and immune response. In breast cancer and other malignancies, alterations of glycan structures and changes in the expression of genes controlling glycosylation were frequently observed, implicating that aberrant glycosylation plays a pivotal role in tumor development and progression. Currently, plant lectins or glycan-specific antibodies are used in immunhistochemistry to characterize the cellular state of glycosylation. Recently, we introduced a novel strategy, named protein domain histochemistry (PDH), using the naturally expressed, human glycoreceptor CLEC10A as a probe to monitor the glycosylation state on formalin-fixed paraffin-embedded tissues (FFPE). CLEC10A belongs to the superfamily of C-type lectins, specifically recognizes terminal N-acetylgalactosamine-(GalNAc) structures and is expressed on dendritic cells and activated macrophages. As tumor-associated cells of the immune system are gaining increasing importance in the regulation of tumor development and progression, we applied CLEC10A as a “reader” of the state of glycosylation in human breast cancer and investigated the value of PDH on patient outcome. Material and Methods: PDH was performed with the human glycoreceptor CLEC10A on FFPE breast cancer tissues (Nollau et al., J Histochem Cytochem 61, 199-205, 2013). In total, 146 primary breast cancers were retrospectively investigated by PDH with 8-year follow-up. Staining intensities were semi-quantitavely assessed by image analysis and statistics were performed with clinicopathological data, including disease-free interval (DFI) and overall survival (OS). Results: Moderate and strong positivity for CLEC10A staining was observed in 36% of breast cancer specimens while 64% of tumors were weakly positive or stained negative. Kaplan Meier analysis demonstrated that positive staining by CLEC10A was significantly associated with increased DFI (p = 0,023) and OS (p = 0,006). DFI time was increased from 67,5 mo (95% ci: 60,1-74,9) to 86,7 mo (95% ci: 78,6-94,8) and OS time from 62,1 mo (95% ci: 55,2-68,9) to 75,8 mo (95% ci: 67,5-84,2), respectively. Multivariate Cox regression analysis proofed positive staining by CLEC10A as an independent prognostic marker for OS (p = 0,025; hazard ratio: 0,45 (95% ci: 0,23-0,90). Discussion: This is the first study evaluating the diagnostic potential of CLEC10A PDH in breast cancer. Positive reactivity of CLEC10A against glycan-epitopes on breast cancer cells was significantly associated with improved patient outcome. Our results warrant further investigations and raise important questions regarding the immune response provoked by the interaction of terminal GalNAc structures in breast cancer with dendritic cells or macrophages expressing CLEC10A. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-05-14.