Neutrophils Driving Unconventional T Cells Mediate Resistance against Murine Sarcomas and Selected Human Tumors

Highlights

• Neutrophils mediate antitumor response by sustaining an IL-12/IFNγ-dependent pathway

• Neutrophils are essential for unconventional αβ T cell (UTCαβ) type 1 polarization

• Type 1 UTC_αβ possess an innate-like phenotype and display antitumor potential in vivo

• Neutrophil infiltration is associated with good prognosis in selected human tumors

Summary

Neutrophils are a component of the tumor microenvironment and have been predominantly associated with cancer progression. Using a genetic approach complemented by adoptive transfer, we found that neutrophils are essential for resistance against primary 3-methylcholantrene-induced carcinogenesis. Neutrophils were essential for the activation of an interferon-γ-dependent pathway of immune resistance, associated with polarization of a subset of CD4⁻ CD8⁻ unconventional αβ T cells (UTC_αβ). Bulk and single-cell RNA sequencing (scRNA-seq) analyses unveiled the innate-like features and diversity of UTC_αβ associated with neutrophil-dependent anti-sarcoma immunity. In selected human tumors, including undifferentiated pleomorphic sarcoma, CSF3R expression, a neutrophil signature and neutrophil infiltration were associated with a type 1 immune response and better clinical outcome. Thus, neutrophils driving UTC_αβ polarization and type 1 immunity are essential for resistance against murine sarcomas and selected human tumors.