Neutrophil conversion to a tumor-killing phenotype underpins effective microbial therapy.
- Publisher:
- American Association for Cancer Research (AACR)
- Publication Type:
- Journal Article
- Citation:
- Cancer Res, 2023, pp. CAN-21-4025
- Issue Date:
- 2023-02-14
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The inflammatory microenvironment of solid tumors creates a pro-tumorigenic milieu that resembles chronic inflammation akin to a subverted wound healing response. Here we investigated the effect of converting the tumor microenvironment from a chronically inflamed state to one of acute microbial inflammation by injecting microbial bioparticles directly into tumors. Intratumoral microbial bioparticle injection led to rapid and dramatic changes in the tumor immune composition, the most striking of which was a substantial increase in the presence of activated neutrophils. In situ photoconversion and intravital microscopy indicated that tumor neutrophils transiently switched from sessile producers of vascular endothelial growth factor to highly motile neutrophils that clustered to make neutrophil-rich domains in the tumor. The neutrophil clusters remodeled tumor tissue and repressed tumor growth. Single cell transcriptional analysis of microbe-stimulated neutrophils showed a profound shift in gene expression towards heightened activation and anti-microbial effector function. Microbe-activated neutrophils also upregulated chemokines known to regulate neutrophil and CD8+ T cell recruitment. Microbial therapy also boosted CD8+ T cell function and enhanced the therapeutic benefit of checkpoint inhibitor therapy in tumor-bearing mice and provided protection in a model of tumor recurrence. These data indicate that one of the major effector mechanisms of microbial therapy is the conversion of tumor neutrophils from a wound healing to an acutely activated cytotoxic phenotype, highlighting a rationale for broader deployment of microbial therapy in the treatment of solid cancers.
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