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.Significance: slan+ monocytes differentiate into macrophages that function as prominent effectors of antibody-mediated tumor cell targeting in lymphoma.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3544/F1.large.jpg Cancer Res; 78(13); 3544-59. ©2018 AACR.
Highlights
Blood monocytes are heterogeneous in terms of phenotype and function and, based on their differential expression of CD14 and CD16, are currently subdivided into classical (CD14þþCD16À), intermediate (CD14þþCD16þ), and nonclassical (CD14dim/ÀCD16þþ) monocytes
Results slanþ cells infiltrate nonHodgkin lymphoma (NHL), nodal diffuse large B-cell lymphoma (DLBCL) Based on our previous results [1], we hypothesized that lymph node accumulation of slanþ cells might occur in nodal lymphomas
For Cohort 1 (CH1) (n 1⁄4 61), the analysis was performed on tissue microarray (TMA) cores, whereas the entire nodal section was available for the analysis of Cohort 2 (CH2) (n 1⁄4 43) and Cohort 3 (CH3) (n 1⁄4 51)
Summary
Blood monocytes are heterogeneous in terms of phenotype and function and, based on their differential expression of CD14 and CD16, are currently subdivided into classical (CD14þþCD16À), intermediate (CD14þþCD16þ), and nonclassical (CD14dim/ÀCD16þþ) monocytes. Recent unsupervised hierarchical clustering has unequivocally proved that slanDCs represent a subset of monocytes [4]. Slanþ monocytes are potent inducers of antigenspecific T-cell responses in vitro [2, 3] and induce a superior Th1/Th17 cell polarization as compared with classical CD1cþ DCs. recent unsupervised hierarchical clustering has unequivocally proved that slanDCs represent a subset of monocytes [4]. Slanþ monocytes are potent inducers of antigenspecific T-cell responses in vitro [2, 3] and induce a superior Th1/Th17 cell polarization as compared with classical CD1cþ DCs Based on their highly specific reactivity to the very stable slan antigen, slanþ cells can be detected in tissues (including archival material) by antibodies known as DD1, DD2, and M-DC8 [1]. The precise functional role of slanþ cells in MTDLNs could not be defined, our in situ analysis clearly indicated that slanþ cells efficiently engulf dead cancer cells
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