2772 - Mechanisms of B-Cell Activity in Tumor Microenvironment

K. Aziz¹, K. Munjal², K. Howe², and M. Yarchoan³; ¹Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, MD, ²Johns Hopkins University, Baltimore, MD, ³Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD

Purpose/Objective(s): Immunotherapies that modulate T cell function have been firmly established in cancer immunotherapy, whereas the potential for B cells in the antitumor immune response is not established. B cell–activating factor (BAFF) is a cytokine belonging to the TNF ligand family that activates B cells, and is linked to autoimmunity. Our preliminary data identified BAFF as a target for enhancing antitumor immunity and formation of tertiary lymphoid structures (TLS) which confers favorable clinical prognosis. BAFF has three known receptors (BAFF-R, TACI and BCMA), but the relative contribution of these receptors to BAFF-mediated antitumor immunity is unknown. We hypothesize that the BAFF-R specifically mediates the positive effects of BAFF on antitumor immunity. Materials/

Methods: We generated BAFF-overexpressing cell lines using genomic editing [KPC-BAFF (pancreas), B16F10-BAFF (melanoma), and PancO2-BAFF (pancreas)] and examined their tumor growth in syngeneic immunocompetent host. We studied the effect of BAFF-overexpression on tumor response when individual receptors are knocked out (KO) using BAFF-R-KO, TACI-KO and BCMA-KO mice. Tumor infiltrating lymphocytes were profiled by CyTOF analysis. Additionally, we characterized the native B cell phenotype in these genetic models. We tested the impact of genetic absence of these individual BAFF receptors as well as BAFF ligand in a TLS formation model. In complementary experiments we characterized the function of candidate cytokines, including BAFF, in the context of de novo TLS induction.
Results: BAFF overexpression suppressed tumor growth in immunocompetent host. Antibody mediated B cell depletion abrogated this effect. Characterization of tumor infiltrating lymphocytes showed BAFF overexpression increased the proportion of total B cells with a shift towards matured phenotype and increased antigen presentation. BAFF ligand knockout abrogated TLS formation in a hepatoma model. Tumor response experiments in receptor knockout mice and characterization of broader immune phenotype is currently in progress.
Conclusion: We have created a preclinical platform to study the anti-tumor effects of BAFF. Successful identification of the BAFF-R as the effector of BAFF-mediated anti-tumor responses will have important implications for clinical translation. Development of agonists for the specific receptor may allow selective modulation of this particular B cell function in context of cancer therapy without perturbation of broad systemic humoral immunity.