Neutrophil Conversion to a Tumor-Killing Phenotype Underpins Effective Microbial Therapy

Area of Science:

• Immunology
• Oncology
• Microbiology

Background:

• Solid tumors possess a chronic inflammatory microenvironment that promotes tumor growth.
• This microenvironment resembles a subverted wound healing response, hindering effective anti-tumor immunity.

Purpose of the Study:

• To investigate the impact of microbial bioparticle injection on the tumor microenvironment.
• To explore the conversion of the tumor microenvironment from chronic to acute microbial inflammation.

Main Methods:

• Intratumoral injection of microbial bioparticles into tumors.
• In situ photoconversion and intravital microscopy to observe neutrophil behavior.
• Single-cell transcriptional analysis of microbe-stimulated neutrophils.
• Assessment of CD8+ T-cell function and checkpoint inhibitor therapy efficacy in mice.

Main Results:

• Microbial bioparticle injection rapidly altered tumor immune composition, significantly increasing activated neutrophils.
• Neutrophils transitioned from sessile VEGF producers to motile cells forming neutrophil-rich domains that remodeled tissue and repressed tumor growth.
• Microbe-activated neutrophils exhibited heightened antimicrobial effector functions and upregulated chemokines for neutrophil and CD8+ T-cell recruitment.
• Microbial therapy enhanced CD8+ T-cell function, improved checkpoint inhibitor therapy outcomes, and provided protection against tumor recurrence.

Conclusions:

• Microbial therapy effectively converts tumor neutrophils to an acutely activated, cytotoxic phenotype, shifting them from a wound-healing role.
• This mechanism provides a strong rationale for the expanded application of microbial therapy in treating solid cancers.