Differential responses of group 2 innate lymphoid cells and T_H2 cells to benralizumab in severe asthma.

Abstract

Severe asthma is a heterogeneous disease with variable treatment responses to biologic therapy. Conventional biomarkers, including blood eosinophil counts and fractional exhaled nitric oxide, only partially capture response heterogeneity. We evaluated the cytokine secretion profiles of group 2 innate lymphoid cells (ILC2s) and T_H2 cells and examined their associations with clinical outcomes after benralizumab therapy. We analyzed 70 patients with severe type 2-high asthma enrolled onto the multicenter Tokyo Asthma Study. Cytokine secretion by ILC2s and T_H2 cells was evaluated by live cell imaging of secretion activity, which enables real-time visualization of cytokine secretion from individual lymphocytes. The frequencies of IL-4-, IL-5-, and IL-13-producing cells were quantified at baseline and after 24 weeks of benralizumab treatment. Clinical responses were primarily assessed by the Asthma Control Questionnaire 5, and patients were classified as experiencing response or not. Japan Registry of Clinical Trials (jRCTs031190237). In type 2-high asthma, ILC2s and T_H2 cells exhibited distinct cytokine secretion profiles with no significant correlation between the two cell populations. Benralizumab selectively suppressed IL-5- and IL-13-producing ILC2s but had little effect on T_H2 cells. Patients with higher baseline frequencies of IL-4-producing T_H2 cells showed limited clinical improvement after benralizumab therapy. In multivariable logistic regression analysis, baseline IL-4-producing T_H2 cell frequency was associated with Asthma Control Questionnaire-defined nonresponse after adjustment for blood eosinophil counts and fractional exhaled nitric oxide. Single-cell functional lymphocyte profiling identifies distinct innate and adaptive type 2 responses to benralizumab and provides complementary information associated with response heterogeneity in severe asthma.