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dc.contributor.authorJung, Keehoon
dc.contributor.authorHeishi, Takahiro
dc.contributor.authorKhan, Omar Fizal
dc.contributor.authorKowalski, Piotr S
dc.contributor.authorIncio, Joao
dc.contributor.authorRahbari, Nuh N.
dc.contributor.authorChung, Euiheon
dc.contributor.authorClark, Jeffrey W.
dc.contributor.authorWillett, Christopher G.
dc.contributor.authorLuster, Andrew D.
dc.contributor.authorYun, Seok Hyun
dc.contributor.authorLanger, Robert S
dc.contributor.authorAnderson, Daniel Griffith
dc.contributor.authorPadera, Timothy P.
dc.contributor.authorJain, Rakesh K.
dc.contributor.authorFukumura, Dai
dc.date.accessioned2019-08-14T15:56:28Z
dc.date.available2019-08-14T15:56:28Z
dc.date.issued2017-07
dc.date.submitted2017-02
dc.identifier.issn0021-9738
dc.identifier.issn1558-8238
dc.identifier.urihttps://hdl.handle.net/1721.1/121987
dc.description.abstractCurrent anti-VEGF therapies for colorectal cancer (CRC) provide limited survival benefit, as tumors rapidly develop resistance to these agents. Here, we have uncovered an immunosuppressive role for nonclassical Ly6C lo monocytes that mediates resistance to anti-VEGFR2 treatment. We found that the chemokine CX3CL1 was upregulated in both human and murine tumors following VEGF signaling blockade, resulting in recruitment of CX3CR1+Ly6C lo monocytes into the tumor. We also found that treatment with VEGFA reduced expression of CX3CL1 in endothelial cells in vitro. Intravital microscopy revealed that CX3CR1 is critical for Ly6C lo monocyte transmigration across the endothelium in murine CRC tumors. Moreover, Ly6C lo monocytes recruit Ly6G + neutrophils via CXCL5 and produce IL-10, which inhibits adaptive immunity. Preventing Ly6C lo monocyte or Ly6G + neutrophil infiltration into tumors enhanced inhibition of tumor growth with anti-VEGFR2 therapy. Furthermore, a gene therapy using a nanoparticle formulated with an siRNA against CX3CL1 reduced Ly6C lo monocyte recruitment and improved outcome of anti-VEGFR2 therapy in mouse CRCs. Our study unveils an immunosuppressive function of Ly6C lo monocytes that, to our knowledge, has yet to be reported in any context. We also reveal molecular mechanisms underlying antiangiogenic treatment resistance, suggesting potential immunomodulatory strategies to enhance the long-term clinical outcome of anti-VEGF therapies.en_US
dc.language.isoen
dc.publisherAmerican Society for Clinical Investigationen_US
dc.relation.isversionofhttp://dx.doi.org/10.1172/jci93182en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourceJournal of Clinical Investigationen_US
dc.titleLy6C[superscript lo] monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapyen_US
dc.typeArticleen_US
dc.identifier.citationJung, Keehoon et al. "Ly6C[superscript lo] monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy." Journal of Clinical Investigation 127, 8 (August 2017): 3039-3051 © 2017 American Society for Clinical Investigationen_US
dc.contributor.departmentDavid H. Koch Institute for Integrative Cancer Research at MITen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Chemical Engineeringen_US
dc.contributor.departmentHarvard University--MIT Division of Health Sciences and Technologyen_US
dc.relation.journalJournal of Clinical Investigationen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2019-08-09T13:29:11Z
dspace.date.submission2019-08-09T13:29:13Z
mit.journal.volume127en_US
mit.journal.issue8en_US


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