Abstract
Aim Rituximab based therapy is the frontline treatment for aggressive B-cell malignancies (Diffuse large B cell lymphoma, DLBCL, Mantle Cell lymphoma, MCL and post-transplant lymphoproliferative disease, PTLD). NK cell mediated ADCC of target B-cells is one of the major modes of Rituximab action. The binding of Rituximab to FcγRIIIa during ADCC is influenced by FcγRIIIa (158 V/F; Valine to Phenylalanine) gene variant, where −158 V is the high affinity variant. However, the clinical relevance of FcγRIIIa gene variant in prediction of Rituximab response in contentious. Here, we analyzed if FcγRIIIa gene variant stratifies Rituximab mediated NK cell response against different B-cell lymphoma targets. Methods Peripheral blood mononuclear cells (MNCs) were obtained from 15 healthy volunteers carrying different FcγRIIIa genotypes (VV/VF n = 9; and FF, n = 6). Multiple representative cell lines of various B-cell lymphoma, and one representing EBV transformed B lymphoblast as a surrogate of PTLD, were selected due to their different phenotypic characteristics. K-562 cells were used as a positive control. MNCs were incubated with rituximab (5 μg/ml) coated different B-cell lymphoma cell lines in a 4hr culture. NK cell response (degranulation and IFN-γ production) was analyzed by multicolor flow cytometry. Results Rituximab mediated NK cell response against all B-cell lymphoma cells was consistently higher in individuals carrying FcγRIIIa 158 V allele (VV or VF genotypes) as compared to individuals carrying FF genotype. However, a considerable heterogeneity was observed in NK cell responses linked to FcγRIIIa 158 V allele against different lymphoma targets. Influence of FcγRIIIa gene variants was most evident against SUDHL-8, a GCB-DLBCL cell line (median % of functional NK cells was 3.2% and 1.1% in individuals with VV/VF and FF genotypes respectively, P = 0.007) and least evident against JeKo, an MCL cell line (5.8% and 4.2% in individuals with VV/VF and FF genotypes respectively, P = 0.27). Conclusions Presence of FcγRIIIa 158 V alleles led to stronger NK cell response to rituximab treated lymphoma cells, though there was a heterogeneity in responses to different lymphoma cell targets. Our findings have strong implications for prediction of Rituximab response in B-cell lymphoma patients.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call