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Functional Reprogramming of Neutrophils within the Brain Tumor Microenvironment by Hypoxia-Driven Histone Lactylation
Alessio Ugolini1,2,3, Alessandra De Leo1,2, Xiaoqing Yu4
1Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida.
Cancer Discovery
|February 27, 2025
Summary
Hypoxia reprograms neutrophils in brain tumors to become immunosuppressive. Targeting histone lactylation, a key mechanism, can block these neutrophils, potentially improving cancer immunotherapy outcomes.
Area of Science:
- Immunology
- Oncology
- Cancer Biology
Background:
- Intratumoral neutrophils, despite heterogeneity, are linked to poor cancer prognosis.
- Tumor microenvironments reprogram neutrophils into immunosuppressive cells, hindering anti-cancer immunity and immunotherapy efficacy.
- Mechanisms of neutrophil reprogramming remain largely unknown.
Purpose of the Study:
- To elucidate the mechanisms by which neutrophils become immunosuppressive within the tumor microenvironment.
- To identify therapeutic targets for counteracting neutrophil-mediated immunosuppression in brain tumors and other malignancies.
Main Methods:
- Analysis of brain tumor-infiltrating neutrophils.
- Investigation of hypoxia-induced metabolic reprogramming in CD71+ neutrophils.
- Assessment of lactate production and histone lactylation.
- Evaluation of targeting histone lactylation using isosafrole.
- Correlation of a gene signature with clinical outcomes.
Main Results:
- A subset of brain tumor-infiltrating neutrophils expressing CD71 exhibited high glycolysis and immunosuppressive properties under hypoxic conditions.
- Hypoxia enhanced glucose metabolism in CD71+ neutrophils, leading to increased lactate production.
- Lactate induced histone lactylation, which upregulated arginase-1 expression, crucial for T-cell suppression.
- Targeting histone lactylation with isosafrole inhibited CD71+ neutrophil immunosuppression, delayed tumor progression, and sensitized tumors to immunotherapy.
- A gene signature of immunosuppressive CD71+ neutrophils correlated with poor clinical outcomes in various human cancers.
Conclusions:
- Hypoxia-driven histone lactylation is a key mechanism for reprogramming neutrophils into immunosuppressive cells in brain tumors.
- Targeting histone lactylation represents a promising therapeutic strategy to overcome neutrophil-induced immunosuppression and enhance cancer immunotherapy.
- This mechanism may be relevant beyond brain tumors, offering broader therapeutic potential.
