Inhibition of colony stimulating factor-1 receptor improves antitumor efficacy of BRAF inhibition.
BACKGROUND
Malignant melanoma is an aggressive tumor type that often develops drug resistance to targeted therapeutics. The production of colony stimulating factor 1 (CSF-1) in tumors recruits myeloid cells such as M2-polarized macrophages and myeloid derived suppressor cells (MDSC), leading to an immune suppressive tumor milieu.


METHODS
We used the syngeneic mouse model of BRAF (V600E) -driven melanoma SM1, which secretes CSF-1, to evaluate the ability of the CSF-1 receptor (CSF-1R) inhibitor PLX3397 to improve the antitumor efficacy of the oncogenic BRAF inhibitor vemurafenib.


RESULTS
Combined BRAF and CSF-1R inhibition resulted in superior antitumor responses compared with either therapy alone. In mice receiving PLX3397 treatment, a dramatic reduction of tumor-infiltrating myeloid cells (TIM) was observed. In this model, we could not detect a direct effect of TIMs or pro-survival cytokines produced by TIMs that could confer resistance to PLX4032 (vemurafenib). However, the macrophage inhibitory effects of PLX3397 treatment in combination with the paradoxical activation of wild type BRAF-expressing immune cells mediated by PLX4032 resulted in more tumor-infiltrating lymphocytes (TIL). Depletion of CD8+ T-cells abrogated the antitumor response to the combination therapy. Furthermore, TILs isolated from SM1 tumors treated with PLX3397 and PLX4032 displayed higher immune potentiating activity.


CONCLUSIONS
The combination of BRAF-targeted therapy with CSF-1R blockade resulted in increased CD8 T-cell responses in the SM1 melanoma model, supporting the ongoing evaluation of this therapeutic combination in patients with BRAF (V600) mutant metastatic melanoma.
Department of Molecular and Medical Pharmacology, University of California Los Angeles (UCLA), Los Angeles, CA, USA. smok1@mdanderson.org.|MD Anderson Cancer Center, Houston, Texas, USA. smok1@mdanderson.org.
Stephen
S
Mok
Department of Molecular and Medical Pharmacology, University of California Los Angeles (UCLA), Los Angeles, CA, USA. jtsoi@mednet.ucla.edu.
Jennifer
J
Tsoi
Department of Surgery, Division of Surgical Oncology, University of California Los Angeles (UCLA), Los Angeles, CA, USA. Richard.Koya@RoswellPark.org.|Roswell Park Cancer Institute, Buffalo, New York, USA. Richard.Koya@RoswellPark.org.
Richard C
RC
Koya
Department of Medicine, Division of Hematology/Oncology, UCLA, University of California Los Angeles (UCLA), 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA, 90095-1782, USA. SHu-Lieskovan@mednet.ucla.edu.
Siwen
S
Hu-Lieskovan
Plexxikon Inc, Berkeley, California, USA. bwest@plexxikon.com.
Brian L
BL
West
Plexxikon Inc, Berkeley, California, USA. gbollag@plexxikon.com.
Gideon
G
Bollag
Department of Molecular and Medical Pharmacology, University of California Los Angeles (UCLA), Los Angeles, CA, USA. TGraeber@mednet.ucla.edu.|Crump Institute for Molecular Imaging, UCLA, University of California Los Angeles (UCLA), Los Angeles, CA, USA. TGraeber@mednet.ucla.edu.|Jonsson Comprehensive Cancer Center (JCCC), University of California Los Angeles (UCLA), Los Angeles, CA, USA. TGraeber@mednet.ucla.edu.
Thomas G
TG
Graeber
Department of Molecular and Medical Pharmacology, University of California Los Angeles (UCLA), Los Angeles, CA, USA. aribas@mednet.ucla.edu.|Department of Surgery, Division of Surgical Oncology, University of California Los Angeles (UCLA), Los Angeles, CA, USA. aribas@mednet.ucla.edu.|Department of Medicine, Division of Hematology/Oncology, UCLA, University of California Los Angeles (UCLA), 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA, 90095-1782, USA. aribas@mednet.ucla.edu.|Jonsson Comprehensive Cancer Center (JCCC), University of California Los Angeles (UCLA), Los Angeles, CA, USA. aribas@mednet.ucla.edu.
Antoni
A
Ribas
D000631:Aminopyridines / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D007211:Indoles / Q000008:administration & dosage; D008213:Lymphocyte Activation; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000008:administration & dosage; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D000077484:Vemurafenib
D000631:Aminopyridines; D007211:Indoles; D011758:Pyrroles; D013449:Sulfonamides; D000077484:Vemurafenib; C000600259:pexidartinib; D016186:Receptor, Macrophage Colony-Stimulating Factor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf