Myeloid expression of adenosine a2A receptor suppresses T and NK cell responses in the solid tumor microenvironment

Simple item page
dc.citation.epage7259en_US
dc.citation.issueNumber24en_US
dc.citation.spage7250en_US
dc.citation.volumeNumber74en_US
dc.contributor.authorCekic, C.en_US
dc.contributor.authorDay, Y.-J.en_US
dc.contributor.authorSag, D.en_US
dc.contributor.authorLinden J.en_US
dc.date.accessioned2016-02-08T10:34:24Z
dc.date.available2016-02-08T10:34:24Z
dc.date.issued2014en_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractHigh concentrations of adenosine in tumor microenvironments inhibit antitumor cytotoxic lymphocyte responses. Although T cells express inhibitory adenosine A2A receptors (A2AR) that suppress their activation and inhibit immune killing of tumors, a role for myeloid cell A2ARs in suppressing the immune response to tumors has yet to be investigated. In this study, we show that the growth of transplanted syngeneic B16F10 melanoma or Lewis lung carcinoma cells is slowed in Adora2af/f-LysMCre+/- mice, which selectively lack myeloid A2ARs. Reduced melanoma growth is associated with significant increases in MHCII and IL12 expression in tumor-associated macrophages and with >90% reductions in IL10 expression in tumor-associated macrophages, dendritic cells (DC), and Ly6C+ or Ly6G+ myeloid-derived suppressor cells (MDSC). Myeloid deletion of A2ARs significantly increases CD44 expression on tumor-associated T cells and natural killer (NK) cells. Depletion of CD8+ T cells or NK cells in tumor-bearing mice indicates that both cell types initially contribute to slowing melanoma growth in mice lacking myeloid A2A receptors, but tumor suppression mediated by CD8+ T cells is more persistent. Myeloid-selective A2AR deletion significantly reduces lung metastasis of melanomas that express luciferase (for in vivo tracking) and ovalbumin (as a model antigen). Reduced metastasis is associated with increased numbers and activation of NK cells and antigen-specific CD8+ T cells in lung in filtrates. Overall, the findings indicate that myeloid cell A2ARs have direct myelosuppressive effects that indirectly contribute to the suppression of T cells and NK cells in primary and metastatic tumor microenvironments. The results indicate that tumor-associated myeloid cells, including macrophages, DCs, and MDSCs all express immunosuppressive A2ARs that are potential targets of adenosine receptor blockers to enhance immune killing of tumors. ©2014 AACR.en_US
dc.description.provenanceMade available in DSpace on 2016-02-08T10:34:24Z (GMT). No. of bitstreams: 1 bilkent-research-paper.pdf: 70227 bytes, checksum: 26e812c6f5156f83f0e77b261a471b5a (MD5) Previous issue date: 2014en
dc.identifier.doi10.1158/0008-5472.CAN-13-3583en_US
dc.identifier.issn0008-5472
dc.identifier.urihttp://hdl.handle.net/11693/24791
dc.language.isoEnglishen_US
dc.publisherAmerican Association for Cancer Research Inc.en_US
dc.relation.isversionofhttp://dx.doi.org/10.1158/0008-5472.CAN-13-3583en_US
dc.source.titleCancer Researchen_US
dc.subjectadenosine A2a receptoren_US
dc.subjectadenosine receptoren_US
dc.subjectHermes antigenen_US
dc.subjectinterleukin 10en_US
dc.subjectinterleukin 12en_US
dc.subjectovalbuminen_US
dc.subjectanimal cellen_US
dc.subjectanimal experimenten_US
dc.subjectArticleen_US
dc.subjectbone marrow cellen_US
dc.subjectCD8+ T lymphocyteen_US
dc.subjectcell killingen_US
dc.subjectcell typeen_US
dc.subjectcontrolled studyen_US
dc.subjectcytotoxic lymphocyteen_US
dc.subjectdendritic cellen_US
dc.subjectex vivo studyen_US
dc.subjectimmune responseen_US
dc.subjectin vivo studyen_US
dc.subjectlung carcinomaen_US
dc.subjectlung metastasisen_US
dc.subjectmacrophageen_US
dc.subjectmelanomaen_US
dc.subjectmouseen_US
dc.subjectnatural killer cellen_US
dc.subjectnonhumanen_US
dc.subjectsolid tumoren_US
dc.subjectT lymphocyteen_US
dc.subjecttumor associated leukocyteen_US
dc.subjecttumor cellen_US
dc.subjecttumor microenvironmenten_US
dc.titleMyeloid expression of adenosine a2A receptor suppresses T and NK cell responses in the solid tumor microenvironmenten_US
dc.typeArticleen_US

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Myeloid expression of adenosine a2A receptor suppresses T and NK cell responses in the solid tumor microenvironment.pdf
Size:
1.29 MB
Format:
Adobe Portable Document Format
Description:
Full printable version
Download

Collections

Scholarly Publications - Molecular Biology and Genetics