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Regulation of myeloid cells by activated T cells determines the efficacy of PD-1 blockade
KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.ORCID iD: 0000-0003-0344-8049
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2016 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 5, no 12, e1232222Article in journal (Refereed) Published
Abstract [en]

Removal of immuno-suppression has been reported to enhance antitumor immunity primed by checkpoint inhibitors. Although PD-1 blockade failed to control tumor growth in a transgenic murine neuroblastoma model, concurrent inhibition of colony stimulating factor 1 receptor (CSF-1R) by BLZ945 reprogrammed suppressive myeloid cells and significantly enhanced therapeutic effects. Microarray analysis of tumor tissues identified a significant increase of T-cell infiltration guided by myeloid cell-derived chemokines CXCL9, 10, and 11. Blocking the responsible chemokine receptor CXCR3 hampered T-cell infiltration and reduced antitumor efficacy of the combination therapy. Multivariate analysis of 59 immune-cell parameters in tumors and spleens detected the correlation between PD-L1-expressing myeloid cells and tumor burden. In vitro, anti-PD-1 antibody Nivolumab in combination with BLZ945 increased the activation of primary human T and NK cells. Importantly, we revealed a previously uncharacterized pathway, in which T cells secreted M-CSF upon PD-1 blockade, leading to enhanced suppressive capacity of monocytes by upregulation of PD-L1 and purinergic enzymes. In multiple datasets of neuroblastoma patients, gene expression of CD73 correlated strongly with myeloid cell markers CD163 and CSF-1R in neuroblastoma tumors, and associated with worse survival in high-risk patients. Altogether, our data reveal the dual role of activated T cells on myeloid cell functions and provide a rationale for the combination therapy of anti-PD-1 antibody with CSF-1R inhibitor.

Place, publisher, year, edition, pages
Taylor & Francis, 2016. Vol. 5, no 12, e1232222
Keyword [en]
Colony stimulating factor 1 receptor (CSF-1R) inhibition, myeloid cell repolarization, neuroblastoma, PD-1 checkpoint blockade, purinergic enzymes
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:kth:diva-202503DOI: 10.1080/2162402X.2016.1232222ISI: 000392846200005Scopus ID: 2-s2.0-84996605806OAI: oai:DiVA.org:kth-202503DiVA: diva2:1077665
Funder
Swedish Childhood Cancer FoundationSwedish Cancer SocietySwedish Research CouncilSwedish Foundation for Strategic Research Knut and Alice Wallenberg Foundation
Note

QC 20170228

Available from: 2017-02-28 Created: 2017-02-28 Last updated: 2017-02-28Bibliographically approved

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