Bouwstra R, He Y, de Boer JW, Kooistra H, Cendrowicz E, Fehrmann RSN, Ammatuna E, Eulenburg C, Nijland M, Huls G, Bremer E, van Meerten T.
Abstract
Addition of rituximab (R) to “CHOP” (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy improved outcome for diffuse large B-cell lymphoma (DLBCL) patients. Approximately 40% of patients that received R-CHOP still succumb to disease due to intrinsic resistance or relapse. A potential negative regulator of DLBCL treatment outcome is the CD47 “don’t eat me” immune checkpoint. To delineate the impact of CD47, we used a clinically and molecularly well-annotated cohort of 939 DLBCL patients, comprising both germinal center B cell (GCB) and non-GCB DLBCL subtypes, treated with either CHOP or R-CHOP. High (above median) CD47 mRNA expression correlated with a detrimental effect on overall survival (OS) when DLBCL patients received R-CHOP therapy (p=0.001), but not when receiving CHOP therapy (p=0.645). Accordingly, patients with low CD47 expression benefited most from addition of rituximab to CHOP (HR, 0.32; CI, 0.21-0.50; P < 0.001). This negative impact of high CD47 expression on OS after R-CHOP treatment was only evident in cancers of non-germinal center B-cell (GCB) origin (HR, 2.09; CI, 1.26-3.47; P = 0.004) and not in the GCB subtype (HR, 1.16; CI, 0.68-1.99; P = 0.58). This differential impact of CD47 in non-GCB and GCB was confirmed in vitro, as macrophage-mediated phagocytosis stimulated by rituximab was augmented by CD47-blocking antibody only in non-GCB cell lines. Thus, high expression of CD47 mRNA limited the benefit of addition of rituximab to CHOP in non-GCB patients and CD47-blockade only augmented rituximab-mediated phagocytosis in non-GCB cell-lines. Patients with non-GCB DLBCL may benefit from CD47-targeted therapy in addition to rituximab.
