title: Regulation of myeloid cells by activated T cells determines the efficacy of PD-1 blockade.
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 ofCD73correlated strongly with myeloid cell markersCD163andCSF-1Rin 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.
authors.affiliation: Childhood Cancer Research Unit, Q6:05, Department of Women's and Children's Health, Karolinska Institutet , Stockholm, Sweden.
authors.forename: Nina
authors.initials: N
authors.lastname: Eissler
authors.affiliation: Cancer Center Karolinska, R8:01, Department of Oncology-Pathology, Karolinska Institutet , Stockholm, Sweden.
authors.forename: Yumeng
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Bioinformatics and Expression Analysis Core Facility, Department of Biosciences and Nutrition, Novum, Karolinska Institutet , Huddinge, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Brodin
authors.affiliation: Division of Proteomics and Nanobiotechnology, Science for Life Laboratory, KTH Royal Institute of Technology , Stockholm, Sweden.
authors.forename: Philippa
authors.initials: P
authors.lastname: Reuterswärd
authors.affiliation: Division of Proteomics and Nanobiotechnology, Science for Life Laboratory, KTH Royal Institute of Technology , Stockholm, Sweden.
authors.forename: Helene
authors.initials: H
authors.lastname: Andersson Svahn
authors.affiliation: Childhood Cancer Research Unit, Q6:05, Department of Women's and Children's Health, Karolinska Institutet , Stockholm, Sweden.
authors.forename: John Inge
authors.initials: JI
authors.lastname: Johnsen
authors.affiliation: Cancer Center Karolinska, R8:01, Department of Oncology-Pathology, Karolinska Institutet , Stockholm, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Kiessling
authors.affiliation: Childhood Cancer Research Unit, Q6:05, Department of Women's and Children's Health, Karolinska Institutet , Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Kogner
keywords: Colony stimulating factor 1 receptor (CSF-1R) inhibition; PD-1 checkpoint blockade; myeloid cell repolarization; neuroblastoma; purinergic enzymes