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Cancer Discov. 2017 Jul;7(7):750-765. doi: 10.1158/2159-8290.CD-16-0778. Epub 2017 Mar 8.

Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Antitumor Innate Immunity.

Author information

1
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.
2
Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
3
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
4
The University of Chicago Comprehensive Cancer Center, Chicago, Illinois.
5
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
6
Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
7
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
8
Harvard Stem Cell Institute, Boston, Massachusetts.
9
Laboratório de Farmacologia Aplicada, PUCRS, Porto Alegre, Brazil.
10
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
11
Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, Massachusetts.
12
Meyer Cancer Center, Weill Cornell Medical College, New York, New York.
13
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
14
Transplant Institute and Immunology Program, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
15
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
16
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
17
Department of Urology, University of Michigan, Ann Arbor, Michigan.
18
Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy.
19
Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
20
Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, Maryland.

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.

PMID:
28274958
PMCID:
PMC5501767
DOI:
10.1158/2159-8290.CD-16-0778
[Indexed for MEDLINE]
Free PMC Article

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