Morphological profiling of T cells predicts clinical response to VLA-4-targeting natalizumab therapy in patients with multiple sclerosis
Listed in
This article is not in any list yet, why not save it to one of your lists.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.
