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

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

doi:10.3390/cancers16030574

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	574
Journal	Cancers
Volume	16
Issue number	3
DOIs	https://doi.org/10.3390/cancers16030574
Publication status	Published - 29 Jan 2024

Bibliographical note

This research was funded by Blood Cancer UK (No. 13045), a CCLG/Little Princess Trust Project Grant (CCLGA 2017 18), the European Regional Development Fund Project ENOCH (No. CZ.02.1.01/0.0/0.0/16_019/0000868) and by the Czech Ministry of Health (DRO: FNOL00098892).

Keywords

rituximab
SPHK1
macrophages
ofatumumab
S1PR1
DLBCL
S1P
phagocytosis
CD20 monoclonal antibodies

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@article{e48178b7ec024b8da0ed92f655407c56,

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

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.",

keywords = "rituximab, SPHK1, macrophages, ofatumumab, S1PR1, DLBCL, S1P, phagocytosis, CD20 monoclonal antibodies",

author = "Perry, {Tracey A.} and Navta Masand and Katerina Vrzalikova and Matthew Pugh and Wenbin Wei and Robert Hollows and Katerina Bouchalova and Mahdi Nohtani and Eanna Fennell and Jan Bouchal and Pamela Kearns and Murray, {Paul G.}",

note = "This research was funded by Blood Cancer UK (No. 13045), a CCLG/Little Princess Trust Project Grant (CCLGA 2017 18), the European Regional Development Fund Project ENOCH (No. CZ.02.1.01/0.0/0.0/16_019/0000868) and by the Czech Ministry of Health (DRO: FNOL00098892).",

year = "2024",

month = jan,

day = "29",

doi = "10.3390/cancers16030574",

language = "English",

volume = "16",

journal = "Cancers",

issn = "2072-6694",

publisher = "MDPI",

number = "3",

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TY - JOUR

T1 - The Oncogenic Lipid Sphingosine-1-Phosphate Impedes the Phagocytosis of Tumor Cells by M1 Macrophages in Diffuse Large B Cell Lymphoma

AU - Perry, Tracey A.

AU - Masand, Navta

AU - Vrzalikova, Katerina

AU - Pugh, Matthew

AU - Wei, Wenbin

AU - Hollows, Robert

AU - Bouchalova, Katerina

AU - Nohtani, Mahdi

AU - Fennell, Eanna

AU - Bouchal, Jan

AU - Kearns, Pamela

AU - Murray, Paul G.

N1 - This research was funded by Blood Cancer UK (No. 13045), a CCLG/Little Princess Trust Project Grant (CCLGA 2017 18), the European Regional Development Fund Project ENOCH (No. CZ.02.1.01/0.0/0.0/16_019/0000868) and by the Czech Ministry of Health (DRO: FNOL00098892).

PY - 2024/1/29

Y1 - 2024/1/29

N2 - 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.

AB - 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.

KW - rituximab

KW - SPHK1

KW - macrophages

KW - ofatumumab

KW - S1PR1

KW - DLBCL

KW - S1P

KW - phagocytosis

KW - CD20 monoclonal antibodies

U2 - 10.3390/cancers16030574

DO - 10.3390/cancers16030574

M3 - Article

SN - 2072-6694

VL - 16

JO - Cancers

JF - Cancers

IS - 3

M1 - 574

ER -

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

Abstract

Bibliographical note

Keywords

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