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

Andrea Ponzetta, Roberta Carriero, Silvia Carnevale, Marialuisa Barbagallo, Martina Molgora, Chiara Perucchini, E. Magrini, Francesca Gianni, P. Kunderfranco, N. Polentarutti, F. Pasqualini, Sabrina Di Marco, Domenico Supino, Clelia Peano, Ferdinando Cananzi, Piergiuseppe Colombo, Silvana Pilotti, Suliman Yousef Alomar, Eduardo Bonavita, Maria Rosaria GaldieroCecilia Garlanda, Alberto Mantovani, Sebastien Jaillon

Research output: Contribution to journalArticlepeer-review

115 Scopus citations


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 (UTCαβ). Bulk and single-cell RNA sequencing (scRNA-seq) analyses unveiled the innate-like features and diversity of UTCαβ 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 UTCαβ polarization and type 1 immunity are essential for resistance against murine sarcomas and selected human tumors. 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 (UTCαβ). Type 1 UTCαβ 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.

Original languageEnglish
Pages (from-to)346-360.e24
Issue number2
StatePublished - Jul 11 2019


  • carcinogenesis
  • innate immunity
  • interleukin-12
  • macrophages
  • neutrophils
  • soft tissue sarcomas
  • tumor immunology
  • unconventional T cells


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