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Slan Monocytes and Macrophages Mediate CD20-Dependent B-Cell

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Slan Monocytes and Macrophages Mediate CD20-Dependent B-Cell Published OnlineFirst May 10, 2018; DOI: 10.1158/0008-5472.CAN-17-2344 Cancer Tumor Biology and Immunology Research slanþ Monocytes and Macrophages Mediate CD20-Dependent B-cell Lymphoma Elimination via ADCC and ADCP William Vermi1,2, Alessandra Micheletti3, Giulia Finotti3, Cristina Tecchio4, Federica Calzetti3, Sara Costa3, Mattia Bugatti1, Stefano Calza5, Claudio Agostinelli6, Stefano Pileri7, Piera Balzarini1, Alessandra Tucci8, Giuseppe Rossi8, Lara Furlani4, Giuseppe Todeschini4, Alberto Zamo9, Fabio Facchetti1, Luisa Lorenzi1, Silvia Lonardi1, and Marco A. Cassatella3 Abstract þ Terminal tissue differentiation and function of slan monocytes in cancer þ + + is largely unexplored. Our recent studies demonstrated that slan mono- slan monocyte slan macrophage cytes differentiate into a distinct subset of dendritic cells (DC) in human CD16A þ tonsils and that slan cells colonize metastatic carcinoma-draining lymph CD32 nodes. Herein, we report by retrospective analysis of multi-institutional þ CD16A CD64 cohorts that slan cells infiltrate various types of non-Hodgkin lymphomas = RTX (NHL), particularly the diffuse large B-cell lymphoma (DLBCL) group, CD20 þ CD20 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 þ þ with DLBCL that peripheral blood slan monocytes, but not CD14 monocytes, increased in number and displayed highly efficient rituxi- Lymphoma cell Lymphoma cell mab-mediated antibody-dependent cellular cytotoxicity, almost equivalent + RTX þ to that exerted by NK cells. Notably, slan monocytes cultured in condi- tioned medium from nodal DLBCL (DCM) acquired a macrophage-like + RTX phenotype, retained CD16 expression, and became very efficient in ritux- imab-mediated antibody-dependent cellular phagocytosis (ADCP). Macro- þ phages derived from DCM-treated CD14 monocytes performed very efficient rituximab-mediated ADCP, however, using different FcgRs from þ those used by slan macrophages. Our observations shed new light on the complexity of the immune microenvironment of DLBCL and demonstrate þ plasticity of slan monocytes homing to cancer tissues. Altogether, data þ identify slan monocytes and macrophages as prominent effectors of antibody-mediated tumor cell targeting in patients with DLBCL. ADCC ADCP fi þ Signi cance: slan monocytes differentiate into macrophages that func- slan+ monocytes perform RTX-mediated antibody-dependent cell-mediated tion as prominent effectors of antibody-mediated tumor cell targeting in cytotoxicity (ADCC) via CD16A, while slan+ macrophages exert RTX-mediated antibody-dependent cellular phagocytosis (ADCP) via CD16A, CD32 and CD64. lymphoma. © 2018 American Association for Cancer Research Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/ 78/13/3544/F1.large.jpg. Cancer Res; 78(13); 3544–59. Ó2018 AACR. 1Section of Pathology, Department of Molecular and Translational Medicine, Note: Supplementary data for this article are available at Cancer Research University of Brescia, Brescia, Italy. 2Department of Pathology and Immu- Online (http://cancerres.aacrjournals.org/). nology, Washington University, Saint Louis, Missouri. 3Section of General A. Micheletti, L. Lorenzi, and S. Lonardi contributed equally to this article. Pathology, Department of Medicine, University of Verona, Verona, Italy. 4Section of Hematology, Department of Medicine, University of Verona, Corresponding Authors: Marco A. Cassatella, Department of Medicine, Verona, Italy. 5Unit of Biostatistics, Department of Molecular and Transla- University of Verona, Strada Le Grazie 4, Verona 37134, Italy. Phone: 3904- tional Medicine, University of Brescia, Brescia, Italy. 6Haematopathology 5802-7130; Fax: 3904-5802-7127; E-mail: [email protected]; and Unit, Department of Experimental Diagnostic and Specialty Medicine, William Vermi, Department of Molecular and Translational Medicine, Section S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. 7Unit of of Pathology, P.le Spedali Civili 1, Brescia 25123, Italy. Phone: 3903-0399-8425; Haematopathology, European Institute of Oncology, 20141 Milan, Italy. Fax: 3903-0399-5377; E-mail: [email protected] 8Division of Haematology, ASST Spedali Civili di Brescia, Brescia, Italy. doi: 10.1158/0008-5472.CAN-17-2344 9Section of Pathology, Department of Public Health and Diagnostics, University of Verona, Verona, Italy. Ó2018 American Association for Cancer Research. 3544 Cancer Res; 78(13) July 1, 2018 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst May 10, 2018; DOI: 10.1158/0008-5472.CAN-17-2344 Role of slanþ Cells in B-cell Lymphoma Introduction Materials and Methods Blood monocytes are heterogeneous in terms of phenotype Tissues þ and function and, based on their differential expression of A tissue screening for slan -cell content was performed on CD14 and CD16, are currently subdivided into classical sections from formalin-fixed paraffin-embedded tissue blocks þþ À þþ þ (CD14 CD16 ), intermediate (CD14 CD16 ), and non- and included reactive (n ¼ 67, Supplementary Table S1) and À þþ classical (CD14dim/ CD16 ) monocytes. Moreover, the neoplastic (n ¼ 151, Supplementary Table S2) lymph nodes from þþ majority of nonclassical (CD14dimCD16 ) monocytes open surgical biopsies retrieved from the Department of Pathol- specifically express the "slan" antigen (1), a carbohydrate ogy, ASST Spedali Civili di Brescia (Brescia, Italy). Neoplastic modification of P-selectin glycoprotein ligand 1 (PSGL-1; lymph nodes included low- and high-grade WHO-defined non- ref. 2). This phenotype, coupled with functional dendritic cell Hodgkin lymphoma (NHL) B- and T-cell lymphomas, as reported (DC)-like features, led Sch€akel and colleagues to originally call in Supplementary Table S2. We also included normal bone them as slanDCs (2, 3). However, recent unsupervised hierar- marrow (n ¼ 10), bone marrow localization of primary nodal chical clustering has unequivocally proved that slanDCs rep- DLBCL (n ¼ 11), as well as 15 cases of primary DLBCL from þ resent a subset of monocytes (4). slan monocytes are potently various extranodal sites. The validation set was represented by proinflammatory, given their capacity to produce higher three multi-institutional cohorts of newly diagnosed and previ- amounts of IL12p70 and TNFa in response to TLR ligands ously untreated, primary DLBCL, two of which with clinical data þþ À þ than classical CD14 CD16 monocytes or CD1c DCs do available (Supplementary Tables S3 and S4). The study has þ (3). slan monocytes are also potent inducers of antigen- been conducted according to the Declaration of Helsinki specific T-cell responses in vitro (2, 3) and induce a superior principles, after having obtained written informed consent þ Th1/Th17 cell polarization as compared with classical CD1c from the patients, and approved by the local ethics board DCs. Importantly, based on their highly specificreactivitytothe (NP906-WV-IMMUNOCANCERhum). þ very stable slan antigen, slan cells can be detected in tissues (including archival material) by antibodies known as DD1, Clinical and demographic features of patients with DLBCL of þ DD2, and M-DC8 (1). To date, slan cells have been detected the validation set in inflamed tissues of patients affected by Crohn disease, Cohort 1 (CH1) included tissue microarray (TMA) cores of 61 rheumatoid arthritis, psoriasis, acute intestinal GVHD samples, DLBCL (from the Haematopathology Unit, Department of Exper- as well as in reactive tonsils and Peyer patches (1, 3, 5, 6). imental, Diagnostic and Specialty Medicine - DIMES, University þ Although the type of differentiation fate of slan monocytes in of Bologna, Bologna, Italy). TMAs were prepared as reported various tissues remains to be established, we have demonstrat- previously (13). Cohort 2 (CH2) included open surgical biopsies þ ed that slan cells isolated from human tonsils, as well as of 43 patients retrieved from the archive of the Department of þ slan monocytes cultured with tonsil-derived medium, show Pathology ASST Spedali Civili di Brescia (Brescia, Italy; Supple- unequivocal terminal differentiation to DCs (5). mentary Table S3). Cohort 3 (CH3) included open surgical þ Recently, we have also reported that slan cells distinctively biopsies of 51 patients retrieved from the archive of the Depart- home to metastatic carcinoma draining lymph nodes (M-TDLNs), ment of Pathology and Diagnostic, Verona University Hospital in close proximity to transformed epithelial cells (1). Our study (Verona, Italy; Supplementary Table S4). For CH1, a panel of þ also revealed that slan cells are absent in primary carcinoma and mouse mAbs toward CD10, BCL6, and MUM1/IRF4 was applied are recruited to lymph nodes following the arrival of cancer cells to define the cell of origin, according to Hans' algorithm (14). IHC þ (1). However, the precise functional role of slan cells in M- and FISH analysis for BCL2, MYC, and BCL6 were used to TDLNs could not be defined, although our in situ analysis clearly subgroup "double expressor" and "double hit" DLBCL, according þ indicated that slan cells efficiently engulf dead cancer cells. to the literature (15, 16) In light of these observations, we pursued the hypothesis that þ slan cells could also infiltrate primary nodal lymphomas, a IHC prediction that preliminarily turned out to be true, particularly
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