1. Academic Validation
  2. Neutrophil-activating therapy for the treatment of cancer

Neutrophil-activating therapy for the treatment of cancer

  • Cancer Cell. 2023 Jan 19;S1535-6108(23)00002-8. doi: 10.1016/j.ccell.2023.01.002.
Ian L Linde 1 Tyler R Prestwood 2 Jingtao Qiu 2 Genay Pilarowski 2 Miles H Linde 3 Xiangyue Zhang 2 Lei Shen 2 Nathan E Reticker-Flynn 2 David Kung-Chun Chiu 2 Lauren Y Sheu 2 Simon Van Deursen 2 Lorna L Tolentino 2 Wen-Chao Song 4 Edgar G Engleman 5
Affiliations

Affiliations

  • 1 Program in Immunology, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA.
  • 2 Department of Pathology, Stanford University, Stanford, CA 94305, USA.
  • 3 Program in Immunology, Stanford University, Stanford, CA 94305, USA.
  • 4 Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 5 Program in Immunology, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA. Electronic address: [email protected].
Abstract

Despite their cytotoxic capacity, neutrophils are often co-opted by cancers to promote immunosuppression, tumor growth, and metastasis. Consequently, these cells have received little attention as potential Cancer immunotherapeutic agents. Here, we demonstrate in mouse models that neutrophils can be harnessed to induce eradication of tumors and reduce metastatic seeding through the combined actions of tumor necrosis factor, CD40 agonist, and tumor-binding antibody. The same combination activates human neutrophils in vitro, enabling their lysis of human tumor cells. Mechanistically, this therapy induces rapid mobilization and tumor infiltration of neutrophils along with complement activation in tumors. Complement component C5a activates neutrophils to produce leukotriene B4, which stimulates Reactive Oxygen Species production via Xanthine Oxidase, resulting in oxidative damage and T cell-independent clearance of multiple tumor types. These data establish neutrophils as potent anti-tumor immune mediators and define an inflammatory pathway that can be harnessed to drive neutrophil-mediated eradication of Cancer.

Keywords

C5a; CD40; cancer immunotherapy; complement; leukotriene B4; neutrophil; reactive oxygen species; tumor immunology; tumor necrosis factor; xanthine oxidase.

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