부산대학교 도서관

Keywords neutrophil; cancer; immunotherapy; anti-CD40; anti-PD-1; IRF1; interferon; SiglecF; lung cancer; single-cell RNA-seq Highlights * Neutrophils can acutely accumulate in tumors during successful immunotherapy * Therapy expands a distinct neutrophil state with an IFN-stimulated gene signature * The neutrophil response requires IRF1 and supports tumor control * Therapy-elicited neutrophil response in patients is associated with better outcome Summary 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.sup.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 IFN[gamma]. 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. Author Affiliation: (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 (4) AGORA Cancer Research Center, Lausanne, Switzerland (5) 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 (8) Department of Oncology, University of Lausanne, Lausanne, Switzerland (9) Ludwig Institute for Cancer Research, Lausanne, Switzerland (10) Department of Oncology, CHUV, Lausanne, Switzerland (11) Swiss Cancer Center Leman, Lausanne, Switzerland * Corresponding author Article History: Received 3 September 2022; Revised 10 January 2023; Accepted 24 February 2023 (miscellaneous) Published: March 30, 2023 (footnote)12 These authors contributed equally (footnote)13 Senior author (footnote)14 Lead contact Byline: Jeremy Gungabeesoon (1,12), Nicolas A. Gort-Freitas (2,12), Máté Kiss (3,4,12), Evangelia Bolli (2,3,4), Marius Messemaker (1,5), Marie Siwicki (1), Mehdi Hicham (3,4), Ruben Bill (2,3,4), Peter Koch (1), Chiara Cianciaruso (2,3,4), Florent Duval (3,4), Christina Pfirschke (1), Michael Mazzola (6), Solange Peters (7,8), Krisztian Homicsko (4,9,10,11), Christopher Garris (1), Ralph Weissleder (1,2), Allon M. Klein [allon_klein@hms.harvard.edu] (2,13,*), Mikael J. Pittet [mikael.pittet@unige.ch] (1,3,4,9,11,13,14,**)