Morphological profiling of T cells predicts clinical response to VLA-4-targeting natalizumab therapy in patients with multiple sclerosis

Abstract

Despite the efficacy of natalizumab in Multiple Sclerosis (MS) treatment, approximately 30% of patients do not respond favorably. Individual heterogeneity of T-cell response to VLA-4 natalizumab-mediated blockade may underlie disparities in treatment efficacy. Here, a high-content cell imaging (HCI) pipeline was implemented to profile the in vitro effects of natalizumab on VLA-4-stimulated leukocytes from MS patients prior to treatment. Unsupervised clustering of image data partially discriminated non-responder MS patients based on morphology, F-actin organization, and signaling-related features in CD8+ T cells. Treatment response was assessed through a Random Forest approach with predictive performance of 91% for a discovery cohort and 70% for a validation cohort. Unfavorable treatment response was associated with the inefficacy of natalizumab to impair the ability of pretreated CD8+ T cells to spread over VCAM-1. Our study unveils that CD8+ T cells from individual MS patients display heterogeneous susceptibility to natalizumab in vitro and highlights the potential of HCI-based pretreatment monitoring to assist individualized treatment prescription.