PMID- 28900008
OWN - NLM
STAT- MEDLINE
DCOM- 20180612
LR  - 20231213
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 114
IP  - 39
DP  - 2017 Sep 26
TI  - Targeting CXCR4-dependent immunosuppressive Ly6C(low) monocytes improves 
      antiangiogenic therapy in colorectal cancer.
PG  - 10455-10460
LID - 10.1073/pnas.1710754114 [doi]
AB  - 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 Ly6C(low) monocytes and not Ly6C(high) monocytes. To 
      selectively deplete individual innate immune cell populations, we targeted key 
      pathways in Ly6C(low) monocytes (Cx3cr1(-/-) mice), Ly6C(high) monocytes 
      (CCR2(-/-) mice), and neutrophils (anti-Ly6G antibody) in combination with CXCR4 
      blockade in SL4 CRCs. Depletion of Ly6C(low) 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 Ly6C(low) 
      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.
FAU - Jung, Keehoon
AU  - Jung K
AD  - Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, 
      Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114.
FAU - Heishi, Takahiro
AU  - Heishi T
AD  - Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, 
      Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114.
FAU - Incio, Joao
AU  - Incio J
AD  - Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, 
      Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114.
FAU - Huang, Yuhui
AU  - Huang Y
AD  - Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, 
      Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114.
FAU - Beech, Elizabeth Y
AU  - Beech EY
AD  - Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, 
      Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114.
FAU - Pinter, Matthias
AU  - Pinter M
AD  - Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, 
      Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114.
FAU - Ho, William W
AU  - Ho WW
AD  - Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, 
      Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114.
AD  - Department of Chemical Engineering, Massachusetts Institute of Technology, 
      Cambridge, MA 02139.
FAU - Kawaguchi, Kosuke
AU  - Kawaguchi K
AD  - Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, 
      Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114.
FAU - Rahbari, Nuh N
AU  - Rahbari NN
AD  - Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, 
      Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114.
FAU - Chung, Euiheon
AU  - Chung E
AD  - Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, 
      Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114.
FAU - Kim, Jun Ki
AU  - Kim JK
AD  - Wellman Center for Photomedicine, Department of Dermatology, Harvard Medical 
      School and Massachusetts General Hospital, Boston, MA 02114.
FAU - Clark, Jeffrey W
AU  - Clark JW
AD  - Department of Hematology/Oncology, Harvard Medical School and Massachusetts 
      General Hospital, Boston, MA 02114.
FAU - Willett, Christopher G
AU  - Willett CG
AD  - Department of Radiation Oncology, Duke University Medical Center, Durham, NC 
      27710.
FAU - Yun, Seok Hyun
AU  - Yun SH
AD  - Wellman Center for Photomedicine, Department of Dermatology, Harvard Medical 
      School and Massachusetts General Hospital, Boston, MA 02114.
AD  - Division of Health Sciences and Technology, Harvard-Massachusetts Institute of 
      Technology, Cambridge, MA 02139.
FAU - Luster, Andrew D
AU  - Luster AD
AD  - Center for Immunology and Inflammatory Diseases, Division of Rheumatology, 
      Allergy and Immunology, Harvard Medical School and Massachusetts General 
      Hospital, Boston, MA 02114.
FAU - Padera, Timothy P
AU  - Padera TP
AD  - Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, 
      Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114.
FAU - Jain, Rakesh K
AU  - Jain RK
AD  - 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.
FAU - Fukumura, Dai
AU  - Fukumura D
AD  - 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.
LA  - eng
GR  - R01 CA204028/CA/NCI NIH HHS/United States
GR  - P01 CA080124/CA/NCI NIH HHS/United States
GR  - R01 CA096915/CA/NCI NIH HHS/United States
GR  - P30 DK043351/DK/NIDDK NIH HHS/United States
GR  - R35 CA197743/CA/NCI NIH HHS/United States
GR  - R01 CA214913/CA/NCI NIH HHS/United States
GR  - R01 CA208205/CA/NCI NIH HHS/United States
GR  - DP2 OD008780/OD/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20170912
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antigens, Ly)
RN  - 0 (Benzylamines)
RN  - 0 (CXCR4 protein, mouse)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Cxcl12 protein, mouse)
RN  - 0 (Cyclams)
RN  - 0 (Heterocyclic Compounds)
RN  - 0 (Ly-6C antigen, mouse)
RN  - 0 (Ly6G antigen, mouse)
RN  - 0 (Receptors, CXCR4)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (vascular endothelial growth factor A, mouse)
RN  - 2S9ZZM9Q9V (Bevacizumab)
RN  - EC 2.7.10.1 (Kdr protein, mouse)
RN  - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
RN  - S915P5499N (plerixafor)
SB  - IM
MH  - Angiogenesis Inhibitors/*pharmacology
MH  - Animals
MH  - Antibodies, Monoclonal/pharmacology
MH  - Antibodies, Monoclonal, Humanized
MH  - Antigens, Ly/metabolism
MH  - Benzylamines
MH  - Bevacizumab/pharmacology
MH  - Cell Proliferation
MH  - Chemokine CXCL12/biosynthesis
MH  - Colorectal Neoplasms/*therapy
MH  - Cyclams
MH  - Heterocyclic Compounds/pharmacology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Monocytes/*immunology
MH  - Neutrophils/*immunology
MH  - Receptors, CXCR4/antagonists & inhibitors/biosynthesis/*metabolism
MH  - Tumor Cells, Cultured
MH  - Vascular Endothelial Growth Factor A/*antagonists & inhibitors
MH  - Vascular Endothelial Growth Factor Receptor-2/*antagonists & inhibitors
MH  - Ramucirumab
PMC - PMC5625928
OTO - NOTNLM
OT  - CXCR4
OT  - Ly6Clow monocyte
OT  - antiangiogenic therapy
OT  - tumor immunity
OT  - tumor microenvironment
COIS- 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.
EDAT- 2017/09/14 06:00
MHDA- 2018/06/13 06:00
PMCR- 2017/09/12
CRDT- 2017/09/14 06:00
PHST- 2017/09/14 06:00 [pubmed]
PHST- 2018/06/13 06:00 [medline]
PHST- 2017/09/14 06:00 [entrez]
PHST- 2017/09/12 00:00 [pmc-release]
AID - 1710754114 [pii]
AID - 201710754 [pii]
AID - 10.1073/pnas.1710754114 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2017 Sep 26;114(39):10455-10460. doi: 
      10.1073/pnas.1710754114. Epub 2017 Sep 12.