Neutrophil-enriched gene signature correlates with teplizumab therapy resistance in different stages of type 1 diabetes

ABSTRACT: Teplizumab, a humanized anti-CD3 monoclonal antibody, represents a major advancement in autoimmune type 1 diabetes (T1D) treatment, capable of delaying clinical onset in stage 2 and preserving beta cell function in early stage 3. However, therapeutic responses are heterogeneous. To better understand this variability, we applied single-cell transcriptomics to paired peripheral blood and pancreas samples from anti-mouse CD3-treated non-obese diabetic (NOD) mice. This analysis identified distinct gene signatures associated with therapy success or resistance, with consistent patterns across both compartments. Success-associated signatures were enriched in NK/CD8⁺ T cells as well as other immune cell types, whereas resistance signatures were predominantly expressed by neutrophils. The immune communities underlying these response signatures were largely confirmed in human whole-blood sequencing data from the AbATE study at 6 months, which assessed teplizumab therapy in stage 3 T1D. Furthermore, baseline expression profiling in both the human TN10 (stage 2) and AbATE (stage 3) cohorts identified immune signatures predictive of therapy response, T cell-enriched signatures in responders and neutrophil-enriched signatures in non-responders, highlighting the critical roles of both adaptive and innate immunity in determining teplizumab outcome. Using an elastic-net logistic regression model, we developed a 26-gene blood-based signature capable of predicting teplizumab response with high accuracy (average AUC = 0.97 across bootstrapped datasets). Together, these findings demonstrate the predictive potential of immune gene signatures and highlight the value of transcriptomic profiling in guiding individualized treatment strategies with teplizumab in T1D.

ORGANISM(S): Mus musculus

PROVIDER: GSE307823 | GEO | 2025/09/16

REPOSITORIES: GEO