Neutrophils Driving Unconventional T Cells Mediate Resistance against Murine Sarcomas and 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.

Graphical Abstract

Highlights

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

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

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  Type 1 UTC _αβ possess an innate-like phenotype and display antitumor potential in vivo

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  Neutrophil infiltration is associated with good prognosis in selected human tumors

Abstract

Tumor-associated neutrophils (TANs) have mainly been portrayed as tumor-promoters. Here, we describe a novel antitumor pathway in which TANs promote IL-12 production by macrophages, leading to type 1 polarization of a subset of unconventional αβ T cell (UTC _αβ). Type 1 UTC _αβ possess an innate-like phenotype and antitumor potential in vivo. In selected human tumors, neutrophil infiltration is associated with type 1 immunity and better clinical outcome.