Functional reprogramming of neutrophils within the brain tumor microenvironment by hypoxia-driven histone lactylation.

in Cancer discovery by Alessio Ugolini, Alessandra De Leo, Xiaoqing Yu, Fabio Scirocchi, Xiaoxian Liu, Barbara Peixoto, Delia Scocozza, Angelica Pace, Michela Perego, Alessandro Gardini, Luca D'Angelo, James K C Liu, Arnold B Etame, Aurelia Rughetti, Marianna Nuti, Antonio Santoro, Michael A Vogelbaum, Jose R Conejo-Garcia, Paulo C Rodriguez, Filippo Veglia

TLDR

  • Highly glycolytic and long-lived neutrophils expressing CD71 are immunosuppressive and contribute to tumor growth and resistance to immunotherapies.
  • Hypoxia and histone lactylation regulate the immunosuppressive properties of CD71+neutrophils, which can be targeted therapeutically.
  • The study identifies histone lactylation as a potential therapeutic target for counteracting neutrophil-induced immunosuppression and improving cancer treatment outcomes.

Abstract

Despite functional heterogeneity, high frequency of intratumoral neutrophils predicts poor clinical outcomes. The tumor microenvironment reprograms neutrophils into immunosuppressive subsets that hinder anti-cancer immunity, thereby contributing to tumor growth and resistance to immunotherapies. However, the mechanisms underlying neutrophil reprogramming remain elusive. Here, we report that the immunosuppressive ability of brain tumor-infiltrating neutrophils was restricted to a highly glycolytic and long-lived subset expressing CD71, which acquired immunosuppressive properties in response to hypoxia. Mechanistically, hypoxia boosted glucose metabolism in CD71+neutrophils, leading to high lactate production. Lactate caused histone lactylation, which subsequently regulated arginase-1 expression, required for T cell suppression. Targeting histone lactylation with the anti-epileptic drug isosafrole blocked CD71+neutrophil immunosuppressive ability, delayed tumor progression and sensitized brain tumors to immunotherapy. A distinctive gene signature characterizing immunosuppressive CD71+neutrophils correlated with adverse clinical outcomes across diverse human malignancies. This study identifies histone lactylation as a potential therapeutic target to counteract neutrophil-induced immunosuppression within tumors.

Overview

  • The study investigates the role of neutrophils in the tumor microenvironment and their reprogramming into immunosuppressive subsets.
  • The researchers focus on brain tumor-infiltrating neutrophils and identify a subset expressing CD71 as having immunosuppressive properties.
  • The study aims to elucidate the mechanisms underlying neutrophil reprogramming and identify potential therapeutic targets to counteract immunosuppression.

Comparative Analysis & Findings

  • The study found that CD71+neutrophils, which are highly glycolytic and long-lived, are responsible for immunosuppression in brain tumors.
  • Hypoxia boosts glucose metabolism in CD71+neutrophils, leading to high lactate production, which regulates arginase-1 expression and induces T cell suppression.
  • Targeting histone lactylation with the anti-epileptic drug isosafrole blocked CD71+neutrophil immunosuppressive ability, delayed tumor progression, and sensitized brain tumors to immunotherapy.

Implications and Future Directions

  • The study highlights the potential therapeutic target of histone lactylation to counteract neutrophil-induced immunosuppression within tumors.
  • Future research directions may involve further investigating the mechanisms of neutrophil reprogramming and identifying additional therapeutic targets.
  • The study's findings may also be applicable to other human malignancies, and further studies are needed to confirm this across diverse tumor types.
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