Regulation of myeloid cells by activated T cells determines the efficacy of PD-1 blockade. (1st December 2016)

• Record Type: Journal Article
• Authors: Eissler, Nina; Mao, Yumeng; Brodin, David; Reuterswärd, Philippa; Andersson Svahn, Helene; Johnsen, John Inge; Kiessling, Rolf; Kogner, Per
• Is Part Of: Oncoimmunology. Volume 5:Number 12(2016)
• Publication Date: 2016-12-01
• Subjects: Colony stimulating factor 1 receptor (CSF-1R) inhibition -- myeloid cell repolarization -- neuroblastoma -- PD-1 checkpoint blockade -- purinergic enzymes; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2016.1232222
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: 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.