Abstract
BackgroundMalignant 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.MethodsWe used the syngeneic mouse model of BRAFV600E-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.ResultsCombined 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.ConclusionsThe 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 BRAFV600 mutant metastatic melanoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1377-8) contains supplementary material, which is available to authorized users.
Highlights
Malignant melanoma is an aggressive tumor type that often develops drug resistance to targeted therapeutics
We observed that adoptive cell transfer (ACT) of melanoma-targeted T-cells induces antitumor responses that are augmented by the BRAF inhibitor PLX4032
Combined therapy with PLX3397 and PLX4032 improves antitumor responses against SM1 tumors C57BL/6 mice with established subcutaneous SM1 tumors were treated with the CSF-1 receptor (CSF-1R) inhibitor PLX3397 and the BRAF inhibitor PLX4032 daily once tumor diameter reached ~5 mm (Figure 1a)
Summary
Malignant melanoma is an aggressive tumor type that often develops drug resistance to targeted therapeutics. Methods: We used the syngeneic mouse model of BRAFV600E-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 Targeted therapies such as the oncogenic BRAF inhibitor PLX4032 (with generic drug name vemurafenib) has resulted in high response rates and improved overall survival in patients with melanoma. Mok et al BMC Cancer (2015) 15:356 to carrying the BRAFV600E oncogene, SM1 has multiple genomic aberrations and share overall similarity to a panel of 108 human melanoma cell lines based on copy number alteration profiling In this model, we observed that adoptive cell transfer (ACT) of melanoma-targeted T-cells induces antitumor responses that are augmented by the BRAF inhibitor PLX4032. We report that PLX3397, a potent tyrosine kinase inhibitor that targets CSF-1R, inhibits the immunosuppressive tumor milieu and facilitates immune responses, resulting in improved antitumor T-cell function [14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
