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Proc Natl Acad Sci U S A. 2017 Sep 26;114(39):10455-10460. doi: 10.1073/pnas.1710754114. Epub 2017 Sep 12.

Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer.

Author information

1
Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114.
2
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
3
Wellman Center for Photomedicine, Department of Dermatology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114.
4
Department of Hematology/Oncology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114.
5
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710.
6
Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, MA 02139.
7
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114.
8
Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114; jain@steele.mgh.harvard.edu dai@steele.mgh.harvard.edu.

Abstract

Antiangiogenic therapy with antibodies against VEGF (bevacizumab) or VEGFR2 (ramucirumab) has been proven efficacious in colorectal cancer (CRC) patients. However, the improvement in overall survival is modest and only in combination with chemotherapy. Thus, there is an urgent need to identify potential underlying mechanisms of resistance specific to antiangiogenic therapy and develop strategies to overcome them. Here we found that anti-VEGFR2 therapy up-regulates both C-X-C chemokine ligand 12 (CXCL12) and C-X-C chemokine receptor 4 (CXCR4) in orthotopic murine CRC models, including SL4 and CT26. Blockade of CXCR4 signaling significantly enhanced treatment efficacy of anti-VEGFR2 treatment in both CRC models. CXCR4 was predominantly expressed in immunosuppressive innate immune cells, which are recruited to CRCs upon anti-VEGFR2 treatment. Blockade of CXCR4 abrogated the recruitment of these innate immune cells. Importantly, these myeloid cells were mostly Ly6Clow monocytes and not Ly6Chigh monocytes. To selectively deplete individual innate immune cell populations, we targeted key pathways in Ly6Clow monocytes (Cx3cr1-/- mice), Ly6Chigh monocytes (CCR2-/- mice), and neutrophils (anti-Ly6G antibody) in combination with CXCR4 blockade in SL4 CRCs. Depletion of Ly6Clow monocytes or neutrophils improved anti-VEGFR2-induced SL4 tumor growth delay similar to the CXCR4 blockade. In CT26 CRCs, highly resistant to anti-VEGFR2 therapy, CXCR4 blockade enhanced anti-VEGFR2-induced tumor growth delay but specific depletion of Ly6G+ neutrophils did not. The discovery of CXCR4-dependent recruitment of Ly6Clow monocytes in tumors unveiled a heretofore unknown mechanism of resistance to anti-VEGF therapies. Our findings also provide a rapidly translatable strategy to enhance the outcome of anti-VEGF cancer therapies.

KEYWORDS:

CXCR4; Ly6Clow monocyte; antiangiogenic therapy; tumor immunity; tumor microenvironment

PMID:
28900008
PMCID:
PMC5625928
DOI:
10.1073/pnas.1710754114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: R.K.J. received consultant fees from Merck, Ophthotech, Pfizer, SPARC, SynDevRx, and XTuit; owns equity in Enlight, Ophthotech, SynDevRx, and XTuit; and serves on the Board of Directors of XTuit and the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund. Neither any reagent nor any funding from these organizations was used in this study.

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