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

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.