{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:19:18Z","timestamp":1792642758813,"version":"4.5.0"},"reference-count":42,"publisher":"Rockefeller University Press","issue":"8","license":[{"start":{"date-parts":[[2019,9,19]],"date-time":"2019-09-19T00:00:00Z","timestamp":1568851200000},"content-version":"vor","delay-in-days":811,"URL":"http:\/\/www.rupress.org\/terms\/"},{"start":{"date-parts":[[2018,2,5]],"date-time":"2018-02-05T00:00:00Z","timestamp":1517788800000},"content-version":"vor","delay-in-days":220,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000884","name":"Cancer Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000884","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009729","name":"Ludwig Cancer Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009729","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1F32CA210568-01"],"award-info":[{"award-number":["1F32CA210568-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01-AI087879-06"],"award-info":[{"award-number":["R01-AI087879-06"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["DP1-GM106409-03"],"award-info":[{"award-number":["DP1-GM106409-03"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01-GM100518-04"],"award-info":[{"award-number":["R01-GM100518-04"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005979","name":"Lustgarten Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005979","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["P01 CA080111"],"award-info":[{"award-number":["P01 CA080111"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001006","name":"Breast Cancer Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001006","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001384","name":"Samuel Waxman Cancer Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001384","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015991","name":"Ludwig Center for Molecular Oncology","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100015991","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,8,7]]},"abstract":"<jats:p>Immunotherapy using checkpoint-blocking antibodies against targets such as CTLA-4 and PD-1 can cure melanoma and non\u2013small cell lung cancer in a subset of patients. The presence of CD8 T cells in the tumor correlates with improved survival. We show that immuno\u2013positron emission tomography (immuno-PET) can visualize tumors by detecting infiltrating lymphocytes and, through longitudinal observation of individual animals, distinguish responding tumors from those that do not respond to therapy. We used 89Zr-labeled PEGylated single-domain antibody fragments (VHHs) specific for CD8 to track the presence of intratumoral CD8+ T cells in the immunotherapy-susceptible B16 melanoma model in response to checkpoint blockade. A 89Zr-labeled PEGylated anti-CD8 VHH detected thymus and secondary lymphoid structures as well as intratumoral CD8 T cells. Animals that responded to CTLA-4 therapy showed a homogeneous distribution of the anti-CD8 PET signal throughout the tumor, whereas more heterogeneous infiltration of CD8 T cells correlated with faster tumor growth and worse responses. To support the validity of these observations, we used two different transplantable breast cancer models, yielding results that conformed with predictions based on the antimelanoma response. It may thus be possible to use immuno-PET and monitor antitumor immune responses as a prognostic tool to predict patient responses to checkpoint therapies.<\/jats:p>","DOI":"10.1084\/jem.20161950","type":"journal-article","created":{"date-parts":[[2017,6,30]],"date-time":"2017-06-30T10:10:13Z","timestamp":1498817413000},"page":"2243-2255","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":233,"title":["Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells"],"prefix":"10.1084","volume":"214","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3708-0038","authenticated-orcid":true,"given":"Mohammad","family":"Rashidian","sequence":"first","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1294-0270","authenticated-orcid":true,"given":"Jessica R.","family":"Ingram","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9266-2009","authenticated-orcid":true,"given":"Michael","family":"Dougan","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 1"},{"name":"Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5688-1132","authenticated-orcid":true,"given":"Anushka","family":"Dongre","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 1"},{"name":"Ludwig Center for Molecular Oncology at MIT, Cambridge, MA 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A.","family":"Whang","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"LeGall","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan J.","family":"Cragnolini","sequence":"additional","affiliation":[{"name":"121Bio, LLC, Lexington MA 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Bierie","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Gostissa","sequence":"additional","affiliation":[{"name":"121Bio, LLC, Lexington MA 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9092-7704","authenticated-orcid":true,"given":"James","family":"Gorman","sequence":"additional","affiliation":[{"name":"121Bio, LLC, Lexington MA 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gijsbert M.","family":"Grotenbreg","sequence":"additional","affiliation":[{"name":"121Bio, LLC, Lexington MA 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atul","family":"Bhan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Massachusetts General Hospital, Boston, MA 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Weinberg","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 1"},{"name":"Ludwig Center for Molecular Oncology at MIT, Cambridge, MA 4"},{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1090-6071","authenticated-orcid":true,"given":"Hidde L.","family":"Ploegh","sequence":"additional","affiliation":[{"name":"Whitehead Institute for Biomedical Research, Cambridge, MA 1"},{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 6"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2017,6,30]]},"reference":[{"key":"2023072604143342200_bib1","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1146\/annurev-immunol-032414-112049","article-title":"Coinhibitory pathways in immunotherapy for cancer","volume":"34","author":"Baumeister","year":"2016","journal-title":"Annu. Rev. Immunol."},{"key":"2023072604143342200_bib2","doi-asserted-by":"publisher","first-page":"11399","DOI":"10.1073\/pnas.1101046108","article-title":"A general strategy for the evolution of bond-forming enzymes using yeast display","volume":"108","author":"Chen","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072604143342200_bib3","doi-asserted-by":"publisher","first-page":"4275","DOI":"10.1073\/pnas.0915174107","article-title":"PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors","volume":"107","author":"Curran","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072604143342200_bib4","doi-asserted-by":"publisher","first-page":"1939","DOI":"10.1517\/17425247.2014.941803","article-title":"Radiolabeled nanobodies as theranostic tools in targeted radionuclide therapy of cancer","volume":"11","author":"D\u2019Huyvetter","year":"2014","journal-title":"Expert Opin. Drug Deliv."},{"key":"2023072604143342200_bib5","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1146\/annurev.immunol.021908.132544","article-title":"Immune therapy for cancer","volume":"27","author":"Dougan","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"2023072604143342200_bib6","doi-asserted-by":"publisher","first-page":"3539","DOI":"10.1073\/pnas.90.8.3539","article-title":"Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity","volume":"90","author":"Dranoff","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072604143342200_bib7","doi-asserted-by":"publisher","first-page":"2296","DOI":"10.1158\/0008-5472.CAN-04-3272","article-title":"Effect of conditional knockout of the type II TGF-\u03b2 receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis","volume":"65","author":"Forrester","year":"2005","journal-title":"Cancer Res."},{"key":"2023072604143342200_bib8","doi-asserted-by":"publisher","first-page":"1787","DOI":"10.1038\/nprot.2013.101","article-title":"Site-specific C-terminal and internal loop labeling of proteins using sortase-mediated reactions","volume":"8","author":"Guimaraes","year":"2013","journal-title":"Nat. Protoc."},{"key":"2023072604143342200_bib9","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1128\/MCB.12.3.954","article-title":"Induction of mammary tumors by expression of polyomavirus middle T oncogene: A transgenic mouse model for metastatic disease","volume":"12","author":"Guy","year":"1992","journal-title":"Mol. Cell. Biol."},{"key":"2023072604143342200_bib10","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/0092-8674(94)90169-4","article-title":"T cell receptor antagonist peptides induce positive selection","volume":"76","author":"Hogquist","year":"1994","journal-title":"Cell."},{"key":"2023072604143342200_bib11","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1038\/nprot.2006.61","article-title":"Generation of T-cell receptor retrogenic mice","volume":"1","author":"Holst","year":"2006","journal-title":"Nat. Protoc."},{"key":"2023072604143342200_bib12","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1007\/s00262-016-1895-5","article-title":"The growing world of CAR T cell trials: a systematic review","volume":"65","author":"Holzinger","year":"2016","journal-title":"Cancer Immunol. Immunother."},{"key":"2023072604143342200_bib13","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1002\/cncr.23712","article-title":"Predominant infiltration of macrophages and CD8+ T cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer","volume":"113","author":"Kawai","year":"2008","journal-title":"Cancer."},{"key":"2023072604143342200_bib14","doi-asserted-by":"publisher","first-page":"452","DOI":"10.2967\/jnumed.113.120873","article-title":"Quantitative immunoPET of prostate cancer xenografts with 89Zr- and 124I-labeled anti-PSCA A11 minibody","volume":"55","author":"Knowles","year":"2014","journal-title":"J. Nucl. Med."},{"key":"2023072604143342200_bib15","doi-asserted-by":"publisher","first-page":"799","DOI":"10.2217\/imt-2016-0029","article-title":"Immune checkpoint inhibitors side effects and management","volume":"8","author":"Kourie","year":"2016","journal-title":"Immunotherapy."},{"key":"2023072604143342200_bib16","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1056\/NEJMoa1504030","article-title":"Combined nivolumab and ipilimumab or monotherapy in untreated melanoma","volume":"373","author":"Larkin","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"2023072604143342200_bib17","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.2967\/jnumed.109.074153","article-title":"Monodispersed DOTA-PEG-conjugated anti-TAG-72 diabody has low kidney uptake and high tumor-to-blood ratios resulting in improved 64Cu PET","volume":"51","author":"Li","year":"2010","journal-title":"J. Nucl. Med."},{"key":"2023072604143342200_bib18","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1021\/bc100464e","article-title":"Site-specific conjugation of monodispersed DOTA-PEGn to a thiolated diabody reveals the effect of increasing peg size on kidney clearance and tumor uptake with improved 64-copper PET imaging","volume":"22","author":"Li","year":"2011","journal-title":"Bioconjug. Chem."},{"key":"2023072604143342200_bib19","doi-asserted-by":"publisher","first-page":"4113","DOI":"10.1158\/0008-5472.CAN-15-2784","article-title":"Immuno-PET imaging of engineered human T cells in tumors","volume":"76","author":"Mall","year":"2016","journal-title":"Cancer Res."},{"key":"2023072604143342200_bib20","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1111\/j.1600-065X.2008.00602.x","article-title":"Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells","volume":"222","author":"Marigo","year":"2008","journal-title":"Immunol. Rev."},{"key":"2023072604143342200_bib21","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/bs.ai.2016.02.004","article-title":"Advances in PET detection of the antitumor T cell response","volume":"131","author":"McCracken","year":"2016","journal-title":"Adv. Immunol."},{"key":"2023072604143342200_bib22","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1007\/s12026-012-8349-8","article-title":"Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function","volume":"55","author":"McNamee","year":"2013","journal-title":"Immunol. Res."},{"key":"2023072604143342200_bib23","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1016\/0092-8674(92)90030-G","article-title":"RAG-1-deficient mice have no mature B and T lymphocytes","volume":"68","author":"Mombaerts","year":"1992","journal-title":"Cell."},{"key":"2023072604143342200_bib24","doi-asserted-by":"publisher","first-page":"4233","DOI":"10.1182\/blood-2007-07-099226","article-title":"Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity","volume":"111","author":"Movahedi","year":"2008","journal-title":"Blood."},{"key":"2023072604143342200_bib25","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1038\/nprot.2014.039","article-title":"A general protocol for the generation of nanobodies for structural biology","volume":"9","author":"Pardon","year":"2014","journal-title":"Nat. Protoc."},{"key":"2023072604143342200_bib26","doi-asserted-by":"publisher","first-page":"1935","DOI":"10.1172\/JCI27745","article-title":"CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells","volume":"116","author":"Quezada","year":"2006","journal-title":"J. Clin. Invest."},{"key":"2023072604143342200_bib27","doi-asserted-by":"publisher","first-page":"6146","DOI":"10.1073\/pnas.1502609112","article-title":"Noninvasive imaging of immune responses","volume":"112","author":"Rashidian","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072604143342200_bib28","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1021\/acscentsci.5b00121","article-title":"Use of 18F-2-fluorodeoxyglucose (FDG) to label antibody fragments for immuno-PET of pancreatic cancer","volume":"1","author":"Rashidian","year":"2015","journal-title":"ACS Central Science."},{"key":"2023072604143342200_bib29","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1002\/anie.201507596","article-title":"Enzyme-mediated modification of single-domain antibodies for imaging modalities with different characteristics","volume":"55","author":"Rashidian","year":"2016","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"2023072604143342200_bib30","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-968-6","volume-title":"Single Domain Antibodies.","author":"Saerens","year":"2012"},{"key":"2023072604143342200_bib31","doi-asserted-by":"publisher","first-page":"18538","DOI":"10.1073\/pnas.0509182102","article-title":"Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+\/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer","volume":"102","author":"Sato","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072604143342200_bib32","doi-asserted-by":"publisher","first-page":"E2646","DOI":"10.1073\/pnas.1604268113","article-title":"Durable antitumor responses to CD47 blockade require adaptive immune stimulation","volume":"113","author":"Sockolosky","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072604143342200_bib33","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1158\/0008-5472.CAN-15-1707","article-title":"An effective immuno-PET imaging method to monitor CD8-dependent responses to immunotherapy","volume":"76","author":"Tavar\u00e9","year":"2016","journal-title":"Cancer Res."},{"key":"2023072604143342200_bib34","doi-asserted-by":"publisher","first-page":"1800","DOI":"10.1038\/nprot.2013.102","article-title":"Site-specific N-terminal labeling of proteins using sortase-mediated reactions","volume":"8","author":"Theile","year":"2013","journal-title":"Nat. Protoc."},{"key":"2023072604143342200_bib35","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.2967\/jnumed.116.186007","article-title":"Noninvasive imaging of human immune responses in a human xenograft model of graft-versus-host disease","volume":"58","author":"Van Elssen","year":"2017","journal-title":"J. Nucl. Med."},{"key":"2023072604143342200_bib36","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.2967\/jnumed.110.075101","article-title":"Renal toxicity of radiolabeled peptides and antibody fragments: Mechanisms, impact on radionuclide therapy, and strategies for prevention","volume":"51","author":"Vegt","year":"2010","journal-title":"J. Nucl. Med."},{"key":"2023072604143342200_bib37","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1146\/annurev-immunol-031210-101324","article-title":"Natural innate and adaptive immunity to cancer","volume":"29","author":"Vesely","year":"2011","journal-title":"Annu. Rev. Immunol."},{"key":"2023072604143342200_bib38","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1038\/nprot.2010.13","article-title":"Conjugation and radiolabeling of monoclonal antibodies with zirconium-89 for PET imaging using the bifunctional chelate p-isothiocyanatobenzyl-desferrioxamine","volume":"5","author":"Vosjan","year":"2010","journal-title":"Nat. Protoc."},{"key":"2023072604143342200_bib39","doi-asserted-by":"publisher","first-page":"355ps16","DOI":"10.1126\/scitranslmed.aaf3936","article-title":"Imaging approaches to optimize molecular therapies","volume":"8","author":"Weissleder","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"2023072604143342200_bib40","doi-asserted-by":"publisher","first-page":"11993","DOI":"10.1073\/pnas.1205427109","article-title":"Preparation of unnatural N-to-N and C-to-C protein fusions","volume":"109","author":"Witte","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072604143342200_bib41","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.ymeth.2013.09.015","article-title":"Engineered antibodies for molecular imaging of cancer","volume":"65","author":"Wu","year":"2014","journal-title":"Methods."},{"key":"2023072604143342200_bib42","doi-asserted-by":"publisher","first-page":"1543","DOI":"10.1007\/s00262-010-0881-6","article-title":"CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection","volume":"59","author":"Yamada","year":"2010","journal-title":"Cancer Immunol. Immunother."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/214\/8\/2243\/1759170\/jem_20161950.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/214\/8\/2243\/1759170\/jem_20161950.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T00:18:47Z","timestamp":1690330727000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/214\/8\/2243\/42510\/Predicting-the-response-to-CTLA-4-blockade-by"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,30]]},"references-count":42,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2017,8,7]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20161950","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6,30]]}}}