title: Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Antitumor Innate Immunity.
abstract: Several kinase inhibitors that target aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in cancer clinical trial patients across several malignancies. Here, we show that cabozantinib rapidly eradicates invasive, poorly differentiated PTEN/p53-deficient murine prostate cancer. This was associated with enhanced release of neutrophil chemotactic factors from tumor cells, including CXCL12 and HMGB1, resulting in robust infiltration of neutrophils into the tumor. Critically, cabozantinib-induced tumor clearance in mice was abolished by antibody-mediated granulocyte depletion or HMGB1 neutralization or blockade of neutrophil chemotaxis with the CXCR4 inhibitor plerixafor. Collectively, these data demonstrate that cabozantinib triggers a neutrophil-mediated anticancer innate immune response, resulting in tumor clearance.Significance:This study is the first to demonstrate that a tyrosine kinase inhibitor can activate neutrophil-mediated antitumor innate immunity, resulting in invasive cancer clearance.Cancer Discov; 7(7); 750-65. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 653.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, Massachusetts. apatnaik1@uchicago.edu.|Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.|Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.|The University of Chicago Comprehensive Cancer Center, Chicago, Illinois.
authors.forename: Akash
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Swanson
authors.affiliation: Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Eva
authors.initials: E
authors.lastname: Csizmadia
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.|Harvard Stem Cell Institute, Boston, Massachusetts.
authors.forename: Aniruddh
authors.initials: A
authors.lastname: Solanki
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.|Harvard Stem Cell Institute, Boston, Massachusetts.
authors.forename: Natalie
authors.initials: N
authors.lastname: Landon-Brace
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.|Laboratório de Farmacologia Aplicada, PUCRS, Porto Alegre, Brazil.
authors.forename: Marina P
authors.initials: MP
authors.lastname: Gehring
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Katja
authors.initials: K
authors.lastname: Helenius
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.|The University of Chicago Comprehensive Cancer Center, Chicago, Illinois.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Olson
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Athalia R
authors.initials: AR
authors.lastname: Pyzer
authors.affiliation: Meyer Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Lily C
authors.initials: LC
authors.lastname: Wang
authors.affiliation: Meyer Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jesse
authors.initials: J
authors.lastname: Novak
authors.affiliation: Transplant Institute and Immunology Program, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Thornley
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Laleh
authors.initials: L
authors.lastname: Montaser
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Timmons
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Morgan
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Yugang
authors.initials: Y
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authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, Massachusetts.|Harvard Stem Cell Institute, Boston, Massachusetts.|Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Levantini
authors.affiliation: Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.|Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
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authors.initials: JG
authors.lastname: Clohessy
authors.affiliation: Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, Maryland.
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authors.lastname: Kelly
authors.affiliation: Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, Massachusetts.|Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
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authors.initials: JM
authors.lastname: Rosenblatt
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, Massachusetts.|Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: David E
authors.initials: DE
authors.lastname: Avigan
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Huihui
authors.initials: H
authors.lastname: Ye
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.|Harvard Stem Cell Institute, Boston, Massachusetts.
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authors.initials: JM
authors.lastname: Karp
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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authors.lastname: Signoretti
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, Massachusetts.|Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
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mesh_terms: D000813:Anilides / Q000008:administration & dosage*; D000818:Animals; D001596:Benzylamines; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000080027:Cyclams; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D006571:Heterocyclic Compounds / Q000008:administration & dosage; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage*; D059016:Tumor Microenvironment / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000813:Anilides; D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D006571:Heterocyclic Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; C558660:cabozantinib; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C088327:plerixafor