In vitro morphological profiling of T cells predicts clinical response to natalizumab therapy in patients with multiple sclerosis

In vitro morphological profiling of T cells predicts clinical response to natalizumab therapy in patients with multiple sclerosis

Abstract Despite the efficacy of natalizumab, which targets the integrin VLA-4, in treating multiple sclerosis (MS), approximately 35% patients with MS present evidence of disease activity two years after treatment initiation. Individual heterogeneity of leukocyte response to VLA-4 on natalizumab-me...

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Main Authors: Beatriz Chaves, Juan Carlo Santos e Silva, Helder Nakaya, Nicolas Socquet-Juglard, Florence Bucciarelli, Guilhèn Prunier, Matheus V. Almeida, Claire Lacouture, Saniya Kari, Anne L. Astier, Marco A. Medeiros, João H. M. Silva, Roland Liblau, Vinicius Cotta-de-Almeida, Loïc Dupré
Format: Article
Language:English
Published: Nature Portfolio 2025-07-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-60224-3
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Summary:Abstract Despite the efficacy of natalizumab, which targets the integrin VLA-4, in treating multiple sclerosis (MS), approximately 35% patients with MS present evidence of disease activity two years after treatment initiation. Individual heterogeneity of leukocyte response to VLA-4 on natalizumab-mediated blockade may underlie disparities in treatment efficacy. Here we use a high-content cell imaging (HCI) pipeline to profile the in vitro effects of natalizumab on VLA-4-stimulated PBMCs from MS patients prior to natalizumab treatment. Unsupervised clustering of image data partially discriminates non-responder MS patients based on morphology, F-actin organization and signaling-related features in CD8+ T cells. Furthermore, through a random forest approach, treatment response can be predicted with a performance of 92% for a discovery cohort and 88% for a validation cohort. Unfavorable treatment response is associated with a distinct actin remodeling response of natalizumab-exposed CD8+ T cells and a residual ability of these cells to spread on VCAM-1. Our study thus 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.
ISSN:2041-1723

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