Immunosurveillance of CCR6+ T-cells predicts treatment response to dimethyl-fumarate: implications for personalized treatment strategies in multiple sclerosis

Abstract

Objective: The field of multiple sclerosis (MS) has seen a tremendous expansion of treatments in the past decade. However, treatment response in individual patients can currently be determined only by waiting for breakthrough disease activity to occur. This highlights a critical need for biomarkers that can predict treatment response and stratify the risk of impeding disease activity before damage is inflicted to the CNS. Here we show that CCR6+CD3+ T-cell surveillance in peripheral blood can be used to discriminate responders and non-responders to dimethyl-fumarate. Methods: A cohort of 101 treatment-naive, dimethyl-fumarate (DMF) treated MS patients and healthy controls was immunophenotyped and then responders and non-responders were determined retrospectively after clinical and radiographic follow up. Receiver operating characteristic (ROC) curve, linear and logistic regression, mixed effects models, and cox proportional hazards were used for the analysis. Results: Among various clinical and immunophenotypic metrics, the percentage of CCR6+CD3+ T-cells was the most significant predictor of impending disease activity. This immunophenotypic metric was able to discriminate responders and non-responders to DMF with an area under the ROC of 0.85 (95% CI: 0.71-0.99), which was higher than that achieved using surrogate metrics for T-helper-1-like T-helper-17 or T-cytotoxic-17 cells. DMF-treated patients with the highest percentage of CCR6+CD3+ T-cells had a significantly higher risk of impending disease activity compared to patients with a low percentage. Interpretation: Changes in CCR6+CD3+ T-cells in the periphery could precede disease activity by many months and potentially serve as an early biomarker of treatment response, at least for DMF. These results have implications for novel personalized treatment strategies in MS.

Immunophenotyping in routine clinical practice for predicting treatment response and adverse events in patients with MS

“…It is well established that DMDs change the cellular immune profile in pwMS ( 17 ). Prior studies have implicated a predictive value of pre-treatment or on-treatment cellular subsets in predicting relapses and/or AEs ( 3 , 7 , 18 , 19 ). While most studies use peripheral blood mononuclear cells (PBMCs) due to their ability to be frozen and stored, studies in fresh blood in the standardized clinical certified laboratory are rare ( 20 ).…”