Interferon-stimulated neutrophils as a predictor of immunotherapy response

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-OrrYuval Shaked

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)253-265.e12
JournalCancer Cell
Volume42
Issue number2
DOIs
StatePublished - 12 Feb 2024

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Keywords

  • Biomarker
  • immunotherapy
  • interferon
  • melanoma
  • neutrophils
  • non-small cell lung cancer
  • response
  • STING

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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