Neutrophil phenotypes and functions in cancer: A consensus statement

Daniela F Quail¹, Borko Amulic², Monowar Aziz³, Betsy J Barnes^{4

5}, Evgeniy Eruslanov⁶, Zvi G Fridlender⁷, Helen S Goodridge⁸, Zvi Granot⁹, Andrés Hidalgo^{10

11}, Anna Huttenlocher^{12

13}, Mariana J Kaplan¹⁴, Ilaria Malanchi¹⁵, Taha Merghoub^{16

17

18

19}, Etienne Meylan^{20

21}, Vivek Mittal^{22

23}, Mikael J Pittet^{24

25

26

27}, Andrea Rubio-Ponce¹¹, Irina A Udalova²⁸, Timo K van den Berg^{29

30}, Denisa D Wagner³¹, Ping Wang³, Arturo Zychlinsky³², Karin E de Visser^{33

34

35}, Mikala Egeblad^{36

35}, Paul Kubes^{37

35

38

39}

Affiliations

¹ Rosalind and Morris Goodman Cancer Institute, Department of Physiology, McGill University, Montreal, Quebec, Canada.
² Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
³ Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY.
⁴ Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, NY.
⁵ Departments of Molecular Medicine and Pediatrics, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY.
⁶ Division of Thoracic Surgery, Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
⁷ Hadassah Medical Center, Institute of Pulmonary Medicine, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
⁸ Board of Governors Regenerative Medicine Institute and Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA.
⁹ Department of Developmental Biology and Cancer Research, Hebrew University of Jerusalem, Jerusalem, Israel.
¹⁰ Vascular Biology and Therapeutics Program and Department of Immunobiology, Yale University School of Medicine, New Haven, CT.
¹¹ Area of Cell and Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
¹² Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI.
¹³ Department of Pediatrics, University of Wisconsin-Madison, Madison, WI.
¹⁴ Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD.
¹⁵ Tumour-Host Interaction Laboratory, The Francis Crick Institute, London, UK.
¹⁶ Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY.
¹⁷ Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY.
¹⁸ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
¹⁹ Weill Cornell Medical College, New York, NY.
²⁰ Lung Cancer and Immuno-Oncology Laboratory, Bordet Cancer Research Laboratories, Institut Jules Bordet, Université Libre de Bruxelles, Anderlecht, Belgium.
²¹ Laboratory of Immunobiology, Université Libre de Bruxelles, Gosselies, Belgium.
²² Department of Cardiothoracic Surgery, Neuberger Berman Foundation Lung Cancer Research Center, Weill Cornell Medicine, New York, NY.
²³ Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY.
²⁴ Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
²⁵ Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
²⁶ Department of Oncology, Geneva University Hospitals, Geneva, Switzerland.
²⁷ AGORA Cancer Research Center, Lausanne, Switzerland.
²⁸ University of Oxford, Kennedy Institute of Rheumatology, Oxford, UK.
²⁹ Laboratory of Immunotherapy, Sanquin Research, Amsterdam, Netherlands.
³⁰ Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Amsterdam, Netherlands.
³¹ Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, MA.
³² Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin, Germany.
³³ Division of Tumour Biology and Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands.
³⁴ Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, Netherlands.
³⁵ Banbury Center meeting organizers, Diverse Functions of Neutrophils in Cancer, Cold Spring Harbor Laboratory, New York, NY.
³⁶ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
³⁷ Department of Pharmacology and Physiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
³⁸ Department of Microbiology, Immunology & Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
³⁹ Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.

PMID: 35522219
PMCID: PMC9086501
DOI: 10.1084/jem.20220011

Review

Neutrophil phenotypes and functions in cancer: A consensus statement

Daniela F Quail et al. J Exp Med. 2022.

. 2022 Jun 6;219(6):e20220011.

doi: 10.1084/jem.20220011. Epub 2022 May 6.

Authors

Affiliations

¹ Rosalind and Morris Goodman Cancer Institute, Department of Physiology, McGill University, Montreal, Quebec, Canada.
² Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
³ Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY.
⁴ Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Manhasset, NY.
⁵ Departments of Molecular Medicine and Pediatrics, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY.
⁶ Division of Thoracic Surgery, Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
⁷ Hadassah Medical Center, Institute of Pulmonary Medicine, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
⁸ Board of Governors Regenerative Medicine Institute and Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA.
⁹ Department of Developmental Biology and Cancer Research, Hebrew University of Jerusalem, Jerusalem, Israel.
¹⁰ Vascular Biology and Therapeutics Program and Department of Immunobiology, Yale University School of Medicine, New Haven, CT.
¹¹ Area of Cell and Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
¹² Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI.
¹³ Department of Pediatrics, University of Wisconsin-Madison, Madison, WI.
¹⁴ Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD.
¹⁵ Tumour-Host Interaction Laboratory, The Francis Crick Institute, London, UK.
¹⁶ Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY.
¹⁷ Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY.
¹⁸ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
¹⁹ Weill Cornell Medical College, New York, NY.
²⁰ Lung Cancer and Immuno-Oncology Laboratory, Bordet Cancer Research Laboratories, Institut Jules Bordet, Université Libre de Bruxelles, Anderlecht, Belgium.
²¹ Laboratory of Immunobiology, Université Libre de Bruxelles, Gosselies, Belgium.
²² Department of Cardiothoracic Surgery, Neuberger Berman Foundation Lung Cancer Research Center, Weill Cornell Medicine, New York, NY.
²³ Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY.
²⁴ Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
²⁵ Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
²⁶ Department of Oncology, Geneva University Hospitals, Geneva, Switzerland.
²⁷ AGORA Cancer Research Center, Lausanne, Switzerland.
²⁸ University of Oxford, Kennedy Institute of Rheumatology, Oxford, UK.
²⁹ Laboratory of Immunotherapy, Sanquin Research, Amsterdam, Netherlands.
³⁰ Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Amsterdam, Netherlands.
³¹ Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, MA.
³² Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin, Germany.
³³ Division of Tumour Biology and Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands.
³⁴ Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, Netherlands.
³⁵ Banbury Center meeting organizers, Diverse Functions of Neutrophils in Cancer, Cold Spring Harbor Laboratory, New York, NY.
³⁶ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
³⁷ Department of Pharmacology and Physiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
³⁸ Department of Microbiology, Immunology & Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
³⁹ Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.

PMID: 35522219
PMCID: PMC9086501
DOI: 10.1084/jem.20220011

Abstract

Neutrophils are the first responders to infection and inflammation and are thus a critical component of innate immune defense. Understanding the behavior of neutrophils as they act within various inflammatory contexts has provided insights into their role in sterile and infectious diseases; however, the field of neutrophils in cancer is comparatively young. Here, we summarize key concepts and current knowledge gaps related to the diverse roles of neutrophils throughout cancer progression. We discuss sources of neutrophil heterogeneity in cancer and provide recommendations on nomenclature for neutrophil states that are distinct in maturation and activation. We address discrepancies in the literature that highlight a need for technical standards that ought to be considered between laboratories. Finally, we review emerging questions in neutrophil biology and innate immunity in cancer. Overall, we emphasize that neutrophils are a more diverse population than previously appreciated and that their role in cancer may present novel unexplored opportunities to treat cancer.

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Conflict of interest statement

Disclosures: E. Eruslanov reported a patent to the use of HLA-DR+CD32hiCD64hi hybrid neutrophils with characteristics of antigen-presenting cells to augment therapy for cancer or infectious diseases pending. Z.G. Fridlender reported “other” from Immunyx outside the submitted work; in addition, Z.G. Fridlender had a patent to ID - 6494-1 licensed "Immunyx." Z. Granot reported personal fees from Immunyx Pharma outside the submitted work. A. Hidalgo is a paid consultant for Flagship Pioneering, which is not related to this work. M.J. Pittet reported personal fees from AstraZeneca, Debiopharm, Elstar Therapeutics, ImmuneOncia, KSQ Therapeutics, MaxiVax, Merck, Molecular Partners, Third Rock Ventures, and Tidal outside the submitted work; in addition, M.J. Pittet has been a consultant for Aileron Therapeutics, Cygnal Therapeutics, and Siamab Therapeutics. T.K van den Berg is an inventor on patent application WO2009/131453 A1, owned by Sanquin Blood Supply Organization, licensed to Byondis BV, related to the targeting of CD47-SIRPα in cancer. D.D. Wagner reported personal fees from Takeda Pharmaceutical and “other” from Neutrolis, SAB during the conduct of the study. K.E. de Visser reported grants from Roche/Genentech and personal fees from Macomics outside the submitted work. M. Egeblad is a member of the research advisory board for brensocatib for Insmed, Inc, a member of the scientific advisory board for Vividion Therapeutics, Inc., and a consultant for Protalix, Inc outside the submitted work. T. Merghoub is a co-founder and holds equity in IMVAQ Therapeutics. He is a consultant of Immunos Therapeutics, ImmunoGenesis, and Pfizer. In addition, T Merghoub has research support from Bristol-Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals Inc., Peregrine Pharmaceuticals Inc., Adaptive Biotechnologies, Leap Therapeutics Inc., and Aprea. He has patents on applications related to work on oncolytic viral therapy, α-virus-based vaccine, neo antigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. No other disclosures were reported.

Figures

**Figure 1.**
**Physiologic and pathologic states that influence neutrophil heterogeneity in cancer.** Tumor-derived factors (e.g., G-CSF, GM-CSF, CXCR2 ligands, TGF-β) and tumor genetics (e.g., *Tp53* loss, oncogenic *Kras*) regulate neutrophil recruitment and activation states in cancer. This is compounded by physiologic (e.g., age, sex, time, tissue, microbes) and pathologic (e.g., obesity, infection, cigarette smoke) states of the host that differentially prime neutrophils to respond to tumor-derived cues. Each of these factors culminate to yield a myriad of different neutrophils “flavors” in cancer that regulate essentially all steps of disease progression, from the primary site to the metastatic niche. Created with BioRender.com.

**Figure 2.**
**Neutrophil maturation and activation. (A)** Comparison of neutrophil states described in landmark studies using single-cell analyses. Overlaid are transcriptional states in normal development and cancer, cell morphology (morph), transcription factor (TF) activity in steady-state (SS) and acute inflammation (AI), neutrotime developmental transition waves, and anatomical location. MB/PM, myeloblasts and promyelocytes; MC, myelocytes; MM, metamyelocytes; BC/SC, band cells and segmented neutrophils. **(B)** Projection of MDSC single-cell RNA-seq data from Veglia et al. (2021a) onto established neutrophil states (comparative datasets obtained from Xie et al. [2020], Immgen [Aran et al., 2019], and Ballesteros et al. [2020]). All intratumoral polymorphonuclear populations referred to as MDSC express canonical signatures of neutrophil maturation and identity states. Created with BioRender.com.

See this image and copyright information in PMC

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Neutrophil phenotypes and functions in cancer: A consensus statement

Affiliations

Neutrophil phenotypes and functions in cancer: A consensus statement

Authors

Affiliations

Abstract

Conflict of interest statement

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