A neutrophil response linked to tumor control in immunotherapy

Jeremy Gungabeesoon; Nicolas A Gort-Freitas; Máté Kiss; Evangelia Bolli; Marius Messemaker; Marie Siwicki; Mehdi Hicham; Ruben Bill; Peter Koch; Chiara Cianciaruso; Florent Duval; Christina Pfirschke; Michael Mazzola; Solange Peters; Krisztian Homicsko; Christopher Garris; Ralph Weissleder; Allon M Klein; Mikael J Pittet

doi:10.1016/j.cell.2023.02.032

A neutrophil response linked to tumor control in immunotherapy

Cell. 2023 Mar 30;186(7):1448-1464.e20. doi: 10.1016/j.cell.2023.02.032.

Authors

Jeremy Gungabeesoon¹, Nicolas A Gort-Freitas², Máté Kiss³, Evangelia Bolli⁴, Marius Messemaker⁵, Marie Siwicki¹, Mehdi Hicham³, Ruben Bill⁴, Peter Koch¹, Chiara Cianciaruso⁴, Florent Duval³, Christina Pfirschke¹, Michael Mazzola⁶, Solange Peters⁷, Krisztian Homicsko⁸, Christopher Garris¹, Ralph Weissleder⁹, Allon M Klein¹⁰, Mikael J Pittet¹¹

Affiliations

¹ Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.
² Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
³ Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, Lausanne, Switzerland.
⁴ Department of Systems Biology, Harvard Medical School, Boston, MA, USA; Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, Lausanne, Switzerland.
⁵ Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA; Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
⁶ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁷ Service of Medical Oncology, Department of Oncology, CHUV, Lausanne, Switzerland; Department of Oncology, University of Lausanne, Lausanne, Switzerland.
⁸ AGORA Cancer Research Center, Lausanne, Switzerland; Ludwig Institute for Cancer Research, Lausanne, Switzerland; Department of Oncology, CHUV, Lausanne, Switzerland; Swiss Cancer Center Leman, Lausanne, Switzerland.
⁹ Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Systems Biology, Harvard Medical School, Boston, MA, USA. Electronic address: allon_klein@hms.harvard.edu.
¹¹ Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA; Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, Lausanne, Switzerland; Ludwig Institute for Cancer Research, Lausanne, Switzerland; Swiss Cancer Center Leman, Lausanne, Switzerland. Electronic address: mikael.pittet@unige.ch.

Abstract

Neutrophils accumulate in solid tumors, and their abundance correlates with poor prognosis. Neutrophils are not homogeneous, however, and could play different roles in cancer therapy. Here, we investigate the role of neutrophils in immunotherapy, leading to tumor control. We show that successful therapies acutely expanded tumor neutrophil numbers. This expansion could be attributed to a Sell^hi state rather than to other neutrophils that accelerate tumor progression. Therapy-elicited neutrophils acquired an interferon gene signature, also seen in human patients, and appeared essential for successful therapy, as loss of the interferon-responsive transcription factor IRF1 in neutrophils led to failure of immunotherapy. The neutrophil response depended on key components of anti-tumor immunity, including BATF3-dependent DCs, IL-12, and IFNγ. In addition, we found that a therapy-elicited systemic neutrophil response positively correlated with disease outcome in lung cancer patients. Thus, we establish a crucial role of a neutrophil state in mediating effective cancer therapy.

Keywords: IRF1; SiglecF; anti-CD40; anti-PD-1; cancer; immunotherapy; interferon; lung cancer; neutrophil; single-cell RNA-seq.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Humans
Immunotherapy
Interferons
Lung Neoplasms* / genetics
Neutrophils*
Signal Transduction / genetics

Substances

Interferons

Abstract

Publication types

MeSH terms

Substances

Grants and funding