title: Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy.
abstract: Colony stimulating factor 1 (CSF-1) recruits tumor-infiltrating myeloid cells (TIM) that suppress tumor immunity, including M2 macrophages and myeloid-derived suppressor cells (MDSC). The CSF-1 receptor (CSF-1R) is a tyrosine kinase that is targetable by small molecule inhibitors such as PLX3397. In this study, we used a syngeneic mouse model of BRAF(V600E)-driven melanoma to evaluate the ability of PLX3397 to improve the efficacy of adoptive cell therapy (ACT). In this model, we found that combined treatment produced superior antitumor responses compared with single treatments. In mice receiving the combined treatment, a dramatic reduction of TIMs and a skewing of MHCII(low) to MHCII(hi) macrophages were observed. Furthermore, mice receiving the combined treatment exhibited an increase in tumor-infiltrating lymphocytes (TIL) and T cells, as revealed by real-time imaging in vivo. In support of these observations, TILs from these mice released higher levels of IFN-γ. In conclusion, CSF-1R blockade with PLX3397 improved the efficacy of ACT immunotherapy by inhibiting the intratumoral accumulation of immunosuppressive macrophages.
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095 (UCLA).
authors.forename: Stephen
authors.initials: S
authors.lastname: Mok
authors.affiliation: Plexxikon Inc., Berkeley, California 94710, U.S.A; Roswell Park Cancer Institute, Buffalo, New York 14263.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Koya
authors.affiliation: Institute for Molecular Medicine, UCLA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Tsui
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095 (UCLA).
authors.forename: Jingying
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, UCLA.
authors.forename: Lídia
authors.initials: L
authors.lastname: Robert
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095 (UCLA).|Institute for Molecular Medicine, UCLA.|Department of Urology, UCLA.|Department of Pediatrics, UCLA.
authors.forename: Lily
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095 (UCLA).|the Jonsson Comprehensive Cancer Center (JCCC) at UCLA.|Institute for Molecular Medicine, UCLA.|Crump Institute for Molecular Imaging, UCLA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Graeber
authors.affiliation: Plexxikon Inc., Berkeley, California 94710, U.S.A; Roswell Park Cancer Institute, Buffalo, New York 14263.
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.affiliation: Plexxikon Inc., Berkeley, California 94710, U.S.A; Roswell Park Cancer Institute, Buffalo, New York 14263.
authors.forename: Gideon
authors.initials: G
authors.lastname: Bollag
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095 (UCLA).|the Jonsson Comprehensive Cancer Center (JCCC) at UCLA.|Surgery, Division of Surgical Oncology, UCLA.|Institute for Molecular Medicine, UCLA.|Department of Medicine, Division of Hematology/Oncology, UCLA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008545:Melanoma / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D047428:Protein Kinase Inhibitors; D016186:Receptor, Macrophage Colony-Stimulating Factor