The role of sphingosine-1-phosphate on macrophage recruitment and function in diffuse large B-cell lymphoma

Perry, Tracey Adams (2019). The role of sphingosine-1-phosphate on macrophage recruitment and function in diffuse large B-cell lymphoma. University of Birmingham. Ph.D.

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Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. Currently, approximately 40% of DLBCL patients treated with standard of care therapies, which include a combination of immunotherapy (Rituximab; R) and chemotherapy (CHOP), will have disease that is refractory or will relapse. Tumour-associated macrophages can phagocytose opsonised DLBCL tumour cells and are therefore centrally important in determining therapeutic outcomes for patients treated with R-CHOP. Recent data from our lab and from others suggests that the modulation of sphingosine-1-phosphate (S1P) signalling may therapeutically benefit some patients with this tumour.
In this study, the effects of S1P on macrophage functions relevant to DLBCL were investigated. Using in vitro phagocytosis assays, S1P signalling through the major receptor, S1PR1, suppressed the phagocytosis of rituximab-opsonised DLBCL cells. However, chemotherapy potently induced monocyte recruitment to DLBCL tumours in vivo and S1PR1 is a primary mediator of monocyte migration both in vitro and in vivo. This work suggests that S1PR1 signalling inhibitors could improve the therapeutic efficacy of rituximab-based therapies for DLBCL patients. However, these drugs should be given only after chemotherapy and before rituximab administration so as to maximise the S1P-mediated recruitment of therapeutic macrophages to the tumour site.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):