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

Publication ,  Journal Article
Jung, K; Heishi, T; Incio, J; Huang, Y; Beech, EY; Pinter, M; Ho, WW; Kawaguchi, K; Rahbari, NN; Chung, E; Kim, JK; Clark, JW; Willett, CG ...
Published in: Proceedings of the National Academy of Sciences of the United States of America
September 2017

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.

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Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

September 2017

Volume

114

Issue

39

Start / End Page

10455 / 10460

Related Subject Headings

  • Vascular Endothelial Growth Factor Receptor-2
  • Vascular Endothelial Growth Factor A
  • Tumor Cells, Cultured
  • Receptors, CXCR4
  • Ramucirumab
  • Neutrophils
  • Monocytes
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
 

Citation

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Jung, K., Heishi, T., Incio, J., Huang, Y., Beech, E. Y., Pinter, M., … Fukumura, D. (2017). Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer. Proceedings of the National Academy of Sciences of the United States of America, 114(39), 10455–10460. https://doi.org/10.1073/pnas.1710754114
Jung, Keehoon, Takahiro Heishi, Joao Incio, Yuhui Huang, Elizabeth Y. Beech, Matthias Pinter, William W. Ho, et al. “Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer.Proceedings of the National Academy of Sciences of the United States of America 114, no. 39 (September 2017): 10455–60. https://doi.org/10.1073/pnas.1710754114.
Jung K, Heishi T, Incio J, Huang Y, Beech EY, Pinter M, et al. Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer. Proceedings of the National Academy of Sciences of the United States of America. 2017 Sep;114(39):10455–60.
Jung, Keehoon, et al. “Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer.Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 39, Sept. 2017, pp. 10455–60. Epmc, doi:10.1073/pnas.1710754114.
Jung K, Heishi T, Incio J, Huang Y, Beech EY, Pinter M, Ho WW, Kawaguchi K, Rahbari NN, Chung E, Kim JK, Clark JW, Willett CG, Yun SH, Luster AD, Padera TP, Jain RK, Fukumura D. Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer. Proceedings of the National Academy of Sciences of the United States of America. 2017 Sep;114(39):10455–10460.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

September 2017

Volume

114

Issue

39

Start / End Page

10455 / 10460

Related Subject Headings

  • Vascular Endothelial Growth Factor Receptor-2
  • Vascular Endothelial Growth Factor A
  • Tumor Cells, Cultured
  • Receptors, CXCR4
  • Ramucirumab
  • Neutrophils
  • Monocytes
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice