Interferon-stimulated neutrophils as a predictor of immunotherapy response.

Abstract

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.

• Authors: Madeleine Benguigui, Tim J Cooper, Prajakta Kalkar, Sagie Schif-Zuck, Ruth Halaban, Antonella Bacchiocchi, Iris Kamer, Abhilash Deo, Bar Manobla, Rotem Menachem, Jozafina Haj-Shomaly, Avital Vorontsova, Ziv Raviv, Chen Buxbaum, Petros Christopoulos, Jair Bar, Michal Lotem, Mario Sznol, Amiram Ariel, Shai S Shen-Orr, Yuval Shaked
• Journal: Cancer cell (Cancer Cell) Vol. 42 Issue 2 Pg. 253-265.e12 (02 12 2024) ISSN: 1878-3686 [Electronic] United States
• PMID: 38181798 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Interferons
• Biomarkers

Topics

• Humans
• Mice
• Animals
• Interferons
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Neutrophils (pathology)
• Lung Neoplasms (drug therapy, pathology)
• Biomarkers
• Immunotherapy