Neutrophil profiling illuminates anti-tumor antigen-presenting potency

Area of Science:

• Immunology
• Cancer Biology
• Cellular Biology

Background:

• Neutrophils are key immune cells with diverse roles in cancer.
• Their short lifespan complicates studying their specific functions in tumors.
• Understanding neutrophil plasticity is crucial for cancer immunotherapy.

Purpose of the Study:

• To investigate the heterogeneity and functional states of neutrophils across various cancer types.
• To identify mechanisms regulating neutrophil functions in the tumor microenvironment.
• To explore therapeutic strategies targeting neutrophils for enhanced cancer treatment.

Main Methods:

• Single-cell RNA sequencing of neutrophils from 17 cancer types (225 samples).
• Integration of transcriptomic data to identify distinct neutrophil states.
• Analysis of leucine metabolism and histone modifications (H3K27ac) in neutrophils.
• Evaluation of neutrophil-based therapies and dietary interventions in murine cancer models.

Main Results:

• Identification of 10 distinct neutrophil states, including inflammation, angiogenesis, and antigen presentation.
• Antigen-presenting neutrophil programs correlated with improved patient survival across most cancers.
• Leucine metabolism and H3K27ac modification were identified as key regulators of antigen presentation.
• Neutrophil delivery or leucine supplementation enhanced anti-PD-1 therapy efficacy in preclinical models.

Conclusions:

• Neutrophils exhibit remarkable functional diversity and plasticity within the cancer microenvironment.
• Antigen-presenting neutrophils represent a promising therapeutic target.
• Modulating neutrophil function through leucine metabolism or cell delivery offers potential strategies to improve cancer immunotherapy.