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<p>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<sup>+</sup> 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.&#xa0;Unfavorable treatment response is associated with a distinct actin remodeling response of natalizumab-exposed CD8<sup>+</sup> T cells and a residual ability of these cells to spread on VCAM-1. Our study thus unveils that CD8<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • 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

摘要

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.