slan+ Monocytes and Macrophages Mediate CD20-Dependent B-cell Lymphoma Elimination via ADCC and ADCP

Abstract

Terminal tissue differentiation and function of slan⁺ monocytes in cancer is largely unexplored. Our recent studies demonstrated that slan⁺ monocytes differentiate into a distinct subset of dendritic cells (DC) in human tonsils and that slan⁺ cells colonize metastatic carcinoma-draining lymph nodes. Herein, we report by retrospective analysis of multi-institutional cohorts that slan⁺ cells infiltrate various types of non-Hodgkin lymphomas (NHL), particularly the diffuse large B-cell lymphoma (DLBCL) group, including the most aggressive, nodal and extranodal, forms. Nodal slan⁺ cells displayed features of either immature DC or macrophages, in the latter case ingesting tumor cells and apoptotic bodies. We also found in patients with DLBCL that peripheral blood slan⁺ monocytes, but not CD14⁺ monocytes, increased in number and displayed highly efficient rituximab-mediated antibody-dependent cellular cytotoxicity, almost equivalent to that exerted by NK cells. Notably, slan⁺ monocytes cultured in conditioned medium from nodal DLBCL (DCM) acquired a macrophage-like phenotype, retained CD16 expression, and became very efficient in rituximab-mediated antibody-dependent cellular phagocytosis (ADCP). Macrophages derived from DCM-treated CD14⁺ monocytes performed very efficient rituximab-mediated ADCP, however, using different FcγRs from those used by slan⁺ macrophages. Our observations shed new light on the complexity of the immune microenvironment of DLBCL and demonstrate plasticity of slan⁺ monocytes homing to cancer tissues. Altogether, data identify slan⁺ monocytes and macrophages as prominent effectors of antibody-mediated tumor cell targeting in patients with DLBCL.<b>Significance:</b> slan⁺ monocytes differentiate into macrophages that function as prominent effectors of antibody-mediated tumor cell targeting in lymphoma.<b>Graphical Abstract:</b> http://cancerres.aacrjournals.org/content/canres/78/13/3544/F1.large.jpg <i>Cancer Res; 78(13); 3544-59. ©2018 AACR</i>.