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 Galdiero; Cecilia Garlanda; Alberto Mantovani; Sebastien Jaillon

doi:10.1016/j.cell.2019.05.047

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

Division of Immunobiology

Research output: Contribution to journal › Article › peer-review

177 Scopus citations

Abstract

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. 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.

Original language	English
Pages (from-to)	346-360.e24
Journal	Cell
Volume	178
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2019.05.047
State	Published - Jul 11 2019

Keywords

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

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10.1016/j.cell.2019.05.047

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Ponzetta, A., Carriero, R., Carnevale, S., Barbagallo, M., Molgora, M., Perucchini, C., Magrini, E., Gianni, F., Kunderfranco, P., Polentarutti, N., Pasqualini, F., Di Marco, S., Supino, D., Peano, C., Cananzi, F., Colombo, P., Pilotti, S., Alomar, S. Y., Bonavita, E., ... Jaillon, S. (2019). Neutrophils Driving Unconventional T Cells Mediate Resistance against Murine Sarcomas and Selected Human Tumors. Cell, 178(2), 346-360.e24. https://doi.org/10.1016/j.cell.2019.05.047

@article{94b908dbfbdb425ebddff5186438d8fb,

title = "Neutrophils Driving Unconventional T Cells Mediate Resistance against Murine Sarcomas and Selected Human Tumors",

abstract = "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.",

keywords = "carcinogenesis, innate immunity, interleukin-12, macrophages, neutrophils, soft tissue sarcomas, tumor immunology, unconventional T cells",

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

note = "Funding Information: We thank Dr. Federico Simone Colombo and Dr. Achille Anselmo for cell sorting experiments, Dr. Javier Cibella for technical help in RNA-seq experiments, Dr. Federica Marchesi, Dr. Enrico Lugli, and Dr. Simone Serio for discussions, and Clarissa Ghirlandini for technical help. This work was supported by the European Research Council (ERC project PHII-669415 ), Ministero dell{\textquoteright}Istruzione, dell{\textquoteright}Universit{\`a} e della Ricerca (MIUR) ( PRIN 2015YYKPNN ), Deanship of Scientific Research at King Saud University ( PEJP-18-11 ), and Fondazione AIRC per la Ricerca sul Cancro ( AIRC IG-19014 and AIRC 5x1000-9962 to A.M. and AIRC ID18475 to S.J.). A.P. is recipient of fellowships from Fondazione Italiana per la Ricerca sul Cancro (FIRC) and Fondazione Umberto Veronesi (FUV). Funding Information: We thank Dr. Federico Simone Colombo and Dr. Achille Anselmo for cell sorting experiments, Dr. Javier Cibella for technical help in RNA-seq experiments, Dr. Federica Marchesi, Dr. Enrico Lugli, and Dr. Simone Serio for discussions, and Clarissa Ghirlandini for technical help. This work was supported by the European Research Council (ERC project PHII-669415), Ministero dell'Istruzione, dell'Universit{\`a} e della Ricerca (MIUR) (PRIN 2015YYKPNN), Deanship of Scientific Research at King Saud University (PEJP-18-11), and Fondazione AIRC per la Ricerca sul Cancro (AIRC IG-19014 and AIRC 5x1000-9962 to A.M. and AIRC ID18475 to S.J.). A.P. is recipient of fellowships from Fondazione Italiana per la Ricerca sul Cancro (FIRC) and Fondazione Umberto Veronesi (FUV). A.P. designed and conducted the experiments and drafted the manuscript. S.C. C. Perucchini, E.M. F.G. N.P. S.D.M. D.S. S.Y.A. E.B. and M.R.G. provided technological support in in vivo experiments. M.B. and M.M. contributed to the experimental design and in vivo experiments. S.P. and F.P. performed the immunohistochemistry on samples of human UPS patients. F.C. and P.C. provided human samples. C. Peano. performed the preparation of samples for single cell RNA-seq analysis. R.C. analyzed bulk and single cell RNA-seq and human public gene expression data. P.K. contributed to and supervised the in silico analyses. C.G. A.M. and S.J. contributed to the experimental design, supervised the study, and revised the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = jul,

day = "11",

doi = "10.1016/j.cell.2019.05.047",

language = "English",

volume = "178",

pages = "346--360.e24",

journal = "Cell",

issn = "0092-8674",

number = "2",

}

Ponzetta, A, Carriero, R, Carnevale, S, Barbagallo, M, Molgora, M, Perucchini, C, Magrini, E, Gianni, F, Kunderfranco, P, Polentarutti, N, Pasqualini, F, Di Marco, S, Supino, D, Peano, C, Cananzi, F, Colombo, P, Pilotti, S, Alomar, SY, Bonavita, E, Galdiero, MR, Garlanda, C, Mantovani, A & Jaillon, S 2019, 'Neutrophils Driving Unconventional T Cells Mediate Resistance against Murine Sarcomas and Selected Human Tumors', Cell, vol. 178, no. 2, pp. 346-360.e24. https://doi.org/10.1016/j.cell.2019.05.047

TY - JOUR

T1 - Neutrophils Driving Unconventional T Cells Mediate Resistance against Murine Sarcomas and Selected Human Tumors

AU - Ponzetta, Andrea

AU - Carriero, Roberta

AU - Carnevale, Silvia

AU - Barbagallo, Marialuisa

AU - Molgora, Martina

AU - Perucchini, Chiara

AU - Magrini, E.

AU - Gianni, Francesca

AU - Kunderfranco, P.

AU - Polentarutti, N.

AU - Pasqualini, F.

AU - Di Marco, Sabrina

AU - Supino, Domenico

AU - Peano, Clelia

AU - Cananzi, Ferdinando

AU - Colombo, Piergiuseppe

AU - Pilotti, Silvana

AU - Alomar, Suliman Yousef

AU - Bonavita, Eduardo

AU - Galdiero, Maria Rosaria

AU - Garlanda, Cecilia

AU - Mantovani, Alberto

AU - Jaillon, Sebastien

N1 - Funding Information: We thank Dr. Federico Simone Colombo and Dr. Achille Anselmo for cell sorting experiments, Dr. Javier Cibella for technical help in RNA-seq experiments, Dr. Federica Marchesi, Dr. Enrico Lugli, and Dr. Simone Serio for discussions, and Clarissa Ghirlandini for technical help. This work was supported by the European Research Council (ERC project PHII-669415 ), Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) ( PRIN 2015YYKPNN ), Deanship of Scientific Research at King Saud University ( PEJP-18-11 ), and Fondazione AIRC per la Ricerca sul Cancro ( AIRC IG-19014 and AIRC 5x1000-9962 to A.M. and AIRC ID18475 to S.J.). A.P. is recipient of fellowships from Fondazione Italiana per la Ricerca sul Cancro (FIRC) and Fondazione Umberto Veronesi (FUV). Funding Information: We thank Dr. Federico Simone Colombo and Dr. Achille Anselmo for cell sorting experiments, Dr. Javier Cibella for technical help in RNA-seq experiments, Dr. Federica Marchesi, Dr. Enrico Lugli, and Dr. Simone Serio for discussions, and Clarissa Ghirlandini for technical help. This work was supported by the European Research Council (ERC project PHII-669415), Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR) (PRIN 2015YYKPNN), Deanship of Scientific Research at King Saud University (PEJP-18-11), and Fondazione AIRC per la Ricerca sul Cancro (AIRC IG-19014 and AIRC 5x1000-9962 to A.M. and AIRC ID18475 to S.J.). A.P. is recipient of fellowships from Fondazione Italiana per la Ricerca sul Cancro (FIRC) and Fondazione Umberto Veronesi (FUV). A.P. designed and conducted the experiments and drafted the manuscript. S.C. C. Perucchini, E.M. F.G. N.P. S.D.M. D.S. S.Y.A. E.B. and M.R.G. provided technological support in in vivo experiments. M.B. and M.M. contributed to the experimental design and in vivo experiments. S.P. and F.P. performed the immunohistochemistry on samples of human UPS patients. F.C. and P.C. provided human samples. C. Peano. performed the preparation of samples for single cell RNA-seq analysis. R.C. analyzed bulk and single cell RNA-seq and human public gene expression data. P.K. contributed to and supervised the in silico analyses. C.G. A.M. and S.J. contributed to the experimental design, supervised the study, and revised the manuscript. The authors declare no competing interests. Publisher Copyright: © 2019 The Authors

PY - 2019/7/11

Y1 - 2019/7/11

N2 - 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.

AB - 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.

KW - carcinogenesis

KW - innate immunity

KW - interleukin-12

KW - macrophages

KW - neutrophils

KW - soft tissue sarcomas

KW - tumor immunology

KW - unconventional T cells

UR - http://www.scopus.com/inward/record.url?scp=85068411899&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2019.05.047

DO - 10.1016/j.cell.2019.05.047

M3 - Article

C2 - 31257026

AN - SCOPUS:85068411899

SN - 0092-8674

VL - 178

SP - 346-360.e24

JO - Cell

JF - Cell

IS - 2

ER -

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

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