Interferon-stimulated neutrophils as a predictor of immunotherapy response

Despite the remarkable success of anti-cancer immunotherapy, its effectiveness remains confined to a subset of patients—emphasizing the importance of predictive biomarkers in clinical decision-making and further mechanistic understanding of treatment response. Current biomarkers, however, lack the power required to accurately stratify patients. Here, we identify interferon-stimulated, Ly6Ehi neutrophils as a blood-borne biomarker of anti-PD1 response in mice at baseline. Ly6Ehi neutrophils are induced by tumor-intrinsic activation of the STING (stimulator of interferon genes) signaling pathway and possess the ability to directly sensitize otherwise non-responsive tumors to anti-PD1 therapy, in part through IL12b-dependent activation of cytotoxic T cells. By translating our pre-clinical findings to a cohort of patients with non-small cell lung cancer and melanoma (n = 109), and to public data (n = 1440), we demonstrate the ability of Ly6Ehi neutrophils to predict immunotherapy response in humans with high accuracy (average AUC ≈ 0.9). Overall, our study identifies a functionally active biomarker for use in both mice and humans. [Display omitted] •Ly6Ehi neutrophils are interferon-stimulated cells present in both mouse and human•Ly6Ehi neutrophils accurately predict immunotherapy outcomes in different cancer types•Activation of the STING pathway in tumors accounts for Ly6Ehi neutrophil enrichment•Ly6Ehi neutrophils sensitize otherwise resistant tumors to immunotherapy in mice A lack of reliable, highly predictive biomarkers remains a major obstacle in immuno-oncology. In this study, Benguigui et al. discover a promising new biomarker: interferon-stimulated, Ly6Ehi neutrophils—whose frequency in the blood of both mice and patients strongly correlates with immunotherapy outcomes across cancer types.