BACKGROUND: A total of 30-40% of diffuse large B cell lymphoma (DLBCL) patients will either not respond to the standard therapy or their disease will recur. The first-line treatment for DLBCL is rituximab and combination chemotherapy. This treatment involves the chemotherapy-induced recruitment of tumor-associated macrophages that recognize and kill rituximab-opsonized DLBCL cells. However, we lack insights into the factors responsible for the recruitment and functionality of macrophages in DLBCL tumors. METHODS: We have studied the effects of the immunomodulatory lipid sphingosine-1-phosphate (S1P) on macrophage activity in DLBCL, both in vitro and in animal models. RESULTS: We show that tumor-derived S1P mediates the chemoattraction of both monocytes and macrophages in vitro and in animal models, an effect that is dependent upon the S1P receptor S1PR1. However, S1P inhibited M1 macrophage-mediated phagocytosis of DLBCL tumor cells opsonized with the CD20 monoclonal antibodies rituximab and ofatumumab, an effect that could be reversed by an S1PR1 inhibitor. CONCLUSIONS: Our data show that S1P signaling can modulate macrophage recruitment and tumor cell killing by anti-CD20 monoclonal antibodies in DLBCL. The administration of S1PR1 inhibitors could enhance the phagocytosis of tumor cells and improve outcomes for patients.

Department of Clinical and Molecular Pathology Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc 77900 Olomouc Czech Republic

Department of Pediatrics Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc 77900 Olomouc Czech Republic

Institute of Cancer and Genomic Sciences University of Birmingham Birmingham B15 2TT UK

Institute of Immunology and Immunotherapy University of Birmingham Birmingham B15 2TT UK

Limerick Digital Cancer Research Centre Health Research Institute and Bernal Institute and School of Medicine University of Limerick Limerick V94 T9PX Ireland

National Institute for Health Research Birmingham Biomedical Research Centre University of Birmingham Birmingham B15 2TT UK

Royal College of Surgeons in Ireland Medical University of Bahrain Manama P O Box 15503 Bahrain

The Palatine Centre Durham University Durham DH1 3LE UK

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