Gungabeesoon, Gort-Freitas, and Kiss et al. demonstrated that neutrophils exhibit remarkable plasticity and could acquire an antitumor phenotype in response to immunotherapy. Immunotherapy-responding tumors showed expansion of distinct neutrophil states in different tumor models, with increases in the expression of an interferon gene signature. The neutrophil response upon immunotherapy was IRF1-dependent and required BATF3-dependent DCs, IL-12, and IFNγ production, as well as the CXCR3 chemokine receptor. The therapy-elicited systemic neutrophil response positively correlated with disease outcome in patients with lung cancer.
Contributed by Shishir Pant
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 Sellhi 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.
Author Info: (1) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (2) Department of Systems Biology, Harvard Medical Sc
Author Info: (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 Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (7) Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, Lausanne, Switzerland. (8) 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. (9) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (10) 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. (11) Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, Lausanne, Switzerland. (12) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (13) Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. (14) Service of Medical Oncology, Department of Oncology, CHUV, Lausanne, Switzerland; Department of Oncology, University of Lausanne, Lausanne, Switzerland. (15) 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. (16) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (17) 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. (18) Department of Systems Biology, Harvard Medical School, Boston, MA, USA. Electronic address: allon_klein@hms.harvard.edu. (19) 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.
