title: Co-inhibition of colony stimulating factor-1 receptor and BRAF oncogene in mouse models of BRAFV600Emelanoma.
abstract: The presence of colony stimulating factor-1 (CSF1)/CSF1 receptor (CSF1R)-driven tumor-infiltrating macrophages and myeloid-derived suppressor cells (MDSCs) is shown to promote targeted therapy resistance. In this study, we demonstrate the superior effect of a combination of CSF1R inhibitor, PLX3397 and BRAF inhibitor, PLX4720, in suppressing primary and metastatic mouse BRAFV600Emelanoma. Using flow cytometry to assess SM1WT1 melanoma-infiltrating leukocytes immediately post therapy, we found that PLX3397 reduced the recruitment of CD11b+Gr1loand CD11b+Gr1intM2-like macrophages, but this was accompanied by an accumulation of CD11b+Gr1hicells. PDL1 expression on remaining myeloid cells potentially dampened the antitumor efficacy of PLX3397 and PLX4720 in combination, since PD1/PDL1 axis blockade improved outcome. We also reveal a role for PLX3397 in reducing tumor-infiltrating lymphocytes, and interestingly, this feature was rescued by the co-administration of PLX4720. Our findings, from three different mouse models of BRAF-mutated melanoma, support clinical approaches that co-target BRAF oncogene and CSF1R.
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland Australia; School of Medicine, The University of Queensland, Herston, Queensland, Australia.
authors.forename: Shin Foong
authors.initials: SF
authors.lastname: Ngiow
authors.affiliation: Department of Pathology, Yale University , New Haven, CT, USA.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Meeth
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute , Herston, Queensland Australia.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Stannard
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute , Herston, Queensland Australia.
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Barkauskas
authors.affiliation: Plexxikon Inc , Berkeley, CA, USA.
authors.forename: Gideon
authors.initials: G
authors.lastname: Bollag
authors.affiliation: Department of Pathology, Yale University, New Haven, CT, USA; Department of Dermatology, Yale University; New Haven, CT, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland Australia; School of Medicine, The University of Queensland, Herston, Queensland, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
keywords: BRAF inhibitor; BRAFV600E; CSF1R; M2 macrophage; PLX3397; PLX4720; melanoma; tumor