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Regulation of myelo...
Regulation of myeloid cells by activated T cells determines the efficacy of PD-1 blockade
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Eissler, Nina (författare)
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- Mao, Yumeng (författare)
- Karolinska Institutet
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- Brodin, David (författare)
- Karolinska Institutet
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- Reuterswärd, Philippa (författare)
- KTH,Proteomik och nanobioteknologi
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- Svahn Andersson, Helene (författare)
- KTH,Proteomik och nanobioteknologi
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- Johnsen, John Inge (författare)
- Karolinska Institutet
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- Kiessling, Rolf (författare)
- Karolinska Institutet
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- Kogner, Per (författare)
- Karolinska Institutet
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(creator_code:org_t)
- Taylor & Francis, 2016
- 2016
- Engelska.
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Ingår i: Oncoimmunology. - : Taylor & Francis. - 2162-4011 .- 2162-402X. ; 5:12
- Relaterad länk:
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
Nyckelord
- Colony stimulating factor 1 receptor (CSF-1R) inhibition
- myeloid cell repolarization
- neuroblastoma
- PD-1 checkpoint blockade
- purinergic enzymes
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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