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dc.contributor.authorTaggart, D
dc.contributor.authorAndreou, T
dc.contributor.authorScott, KJ
dc.contributor.authorWilliams, J
dc.contributor.authorRippaus, N
dc.contributor.authorBrownlie, RJ
dc.contributor.authorIlett, EJ
dc.contributor.authorSalmond, RJ
dc.contributor.authorMelcher, A
dc.contributor.authorLorger, M
dc.date.accessioned2018-02-13T12:57:50Z
dc.date.issued2018-02
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2018, 115 (7), pp. E1540 - E1549
dc.identifier.issn0027-8424
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1051
dc.identifier.eissn1091-6490
dc.identifier.doi10.1073/pnas.1714089115
dc.description.abstractInhibition of immune checkpoints programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on T cells results in durable antitumor activity in melanoma patients. Despite high frequency of melanoma brain metastases (BrM) and associated poor prognosis, the activity and mechanisms of immune checkpoint inhibitors (ICI) in metastatic tumors that develop within the "immune specialized" brain microenvironment, remain elusive. We established a melanoma tumor transplantation model with intracranial plus extracranial (subcutaneous) tumor, mimicking the clinically observed coexistence of metastases inside and outside the brain. Strikingly, intracranial ICI efficacy was observed only when extracranial tumor was present. Extracranial tumor was also required for ICI-induced increase in CD8+ T cells, macrophages, and microglia in brain tumors, and for up-regulation of immune-regulatory genes. Combined PD-1/CTLA-4 blockade had a superior intracranial efficacy over the two monotherapies. Cell depletion studies revealed that NK cells and CD8+ T cells were required for intracranial anti-PD-1/anti-CTLA-4 efficacy. Rather than enhancing CD8+ T cell activation and expansion within intracranial tumors, PD-1/CTLA-4 blockade dramatically (∼14-fold) increased the trafficking of CD8+ T cells to the brain. This was mainly through the peripheral expansion of homing-competent effector CD8+ T cells and potentially further enhanced through up-regulation of T cell entry receptors intercellular adhesion molecule 1 and vascular adhesion molecule 1 on tumor vasculature. Our study indicates that extracranial activation/release of CD8+ T cells from PD-1/CTLA-4 inhibition and potentiation of their recruitment to the brain are paramount to the intracranial anti-PD-1/anti-CTLA-4 activity, suggesting augmentation of these processes as an immune therapy-enhancing strategy in metastatic brain cancer.
dc.formatPrint-Electronic
dc.format.extentE1540 - E1549
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.subjectCD8-Positive T-Lymphocytes
dc.subjectT-Lymphocytes, Cytotoxic
dc.subjectLymphocytes, Tumor-Infiltrating
dc.subjectTumor Cells, Cultured
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectMice
dc.subjectMelanoma, Experimental
dc.subjectBrain Neoplasms
dc.subjectSkin Neoplasms
dc.subjectAntibodies, Monoclonal
dc.subjectTumor Burden
dc.subjectFemale
dc.subjectT-Lymphocytes, Regulatory
dc.subjectGranzymes
dc.subjectProgrammed Cell Death 1 Receptor
dc.titleAnti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking.
dc.typeJournal Article
dcterms.dateAccepted2018-02-13
rioxxterms.versionofrecord10.1073/pnas.1714089115
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
rioxxterms.licenseref.startdate2018-02
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfProceedings of the National Academy of Sciences of the United States of America
pubs.issue7
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy/Translational Immunotherapy (TL)
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy/Translational Immunotherapy (TL)
pubs.publication-statusPublished
pubs.volume115
pubs.embargo.termsNot known
icr.researchteamTranslational Immunotherapyen_US
dc.contributor.icrauthorMelcher, Alanen


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