Abstract 544: Follicular Dendritic Cells promote tumor B cell survival through BAFF mediated anti-apoptotic signaling in the tumor microenvironment of Follicular Lymphoma

Follicular lymphoma (FL) is the second most common B-cell non-Hodgkin9s lymphoma that responds well to initial therapy but has a continuous pattern of relapses and remissions and eventually leads to a fatal outcome in the majority of the patients. Preliminary meta-analysis of microarray data from various gene expression studies led to the identification of unique features of FL such as up regulation in genes associated with TNFSF family (BAFF, APRIL), BMP signaling pathway, 14-3-3-mediated signaling, NFκB signaling, NFAT signaling and IL-4 signaling. The results indicate that some of the gene expression patterns are possibly derived from infiltrating T cells, lymphoma associated macrophages (LAM) or follicular dendritic cells (FDC). FDCs play a vital role in the maturation of normal B cells in the germinal center. FDCs have been found to be the common source for both BAFF and APRIL. Three main receptors TACI, BCMA and BAFF-R that recognize these factors are known to be expressed by many immune cell types including GC B cells. Whether the levels of expression of BAFF-R and TACI are important for tumor cell survival is not clear. From immunohistochemistry based studies BAFF-R has been demonstrated to be up regulated in tumor B cells from FL patients but absent in grade 3 FL and DLBCL. We have detected elevated serum levels of BAFF in FL patients (n=10) compared with normal donors (n=10). Further cell surface staining for BAFF-R was significantly higher in CD20+ tumor B cells from FL compared to normal donor tonsil derived B cells. We employed HK cell line (human FDC phenotype) to study the cell to cell interactions in a co-culture system with either FL tumor or normal donor tonsil derived B cells. HK cells behave like typical FDCs and secrete BAFF and APRIL into the conditioned medium that was detected and confirmed by ELISA. We found that FL derived tumor B cells survived significantly longer in co-culture with HK cells (10 to 14 days) compared to when cultured alone in vitro (5 to 7 days) based on Annexin-V FITC analysis by flowcytometry. BrdU cell proliferation assay showed that there was sustainable cell growth and mitosis over this two week period. In conclusion we determined a positive correlation between levels of BAFF in the conditioned medium and tumor B cell survival suggesting a role for BAFF mediated anti-apoptotic signaling. Future experiments will determine other factors that may have a role in contributing to tumor B cell survival and further study the mechanism of cell survival in this co-culture system. This study holds much promise for developing newer therapeutic targets like monoclonal antibodies to cell surface receptors that can block the anti-apoptotic signaling in vivo thereby negating the supportive role of tumor microenvironment. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 544.