The Oncogenic Lipid Sphingosine-1-Phosphate Impedes the Phagocytosis of Tumor Cells by M1 Macrophages in Diffuse Large B Cell Lymphoma

Perry, Tracey A.; Masand, Navta; Vrzalikova, Katerina; Pugh, Matthew; Wei, Wenbin; Hollows, Robert; Bouchalova, Katerina; Nohtani, Mahdi; Fennell, Eanna; Bouchal, Jan; Kearns, Pamela; Murray, Paul G.

Abstract

Simple Summary: Diffuse large B cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, is clinically aggressive and associated with poor patient outcomes. Antagonists of the small oncogenic lipid sphingosine-1-phosphate (S1P) are already in the clinic and have been suggested to have therapeutic potential in DLBCL. We have studied the impact of S1P signaling on the recruitment of macrophages and their phagocytic functions following the treatment of DLBCL cells with CD20-targeting antibodies. We have shown that tumor-derived S1P is a major chemoattractant for monocytes and macrophages, both in vitro and in animal models of DLBCL, an effect mediated by the S1P receptor S1PR1. However, S1P also robustly inhibited the phagocytosis of antibody-treated tumor cells by M1 macrophages. Future experiments could be directed toward investigating the therapeutic effects of blocking S1P–S1PR1 signaling in combination with chemotherapy and CD20-targeting antibodies. Abstract: 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.

Citation

Perry, T. A., Masand, N., Vrzalikova, K., Pugh, M., Wei, W., Hollows, R., …Murray, P. G. (2024). The Oncogenic Lipid Sphingosine-1-Phosphate Impedes the Phagocytosis of Tumor Cells by M1 Macrophages in Diffuse Large B Cell Lymphoma. Cancers, 16(3), Article 574. https://doi.org/10.3390/cancers16030574

• Journal Article Type: Article
• Acceptance Date: Jan 25, 2024
• Online Publication Date: Jan 29, 2024
• Publication Date: Jan 29, 2024
• Deposit Date: Mar 14, 2024
• Publicly Available Date: Mar 14, 2024
• Journal: Cancers
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 16
• Issue: 3
• Article Number: 574
• DOI: https://doi.org/10.3390/cancers16030574
• Keywords: rituximab, SPHK1, macrophages, ofatumumab, S1PR1, DLBCL, S1P, phagocytosis, CD20 monoclonal antibodies
• Public URL: https://durham-repository.worktribe.com/output/2234513