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- Title
Inhibition of colony stimulating factor-1 receptor improves antitumor efficacy of BRAF inhibition.
- Authors
Mok, Stephen; Tsoi, Jennifer; Koya, Richard C; Hu-Lieskovan, Siwen; West, Brian L; Bollag, Gideon; Graeber, Thomas G; Ribas, Antoni
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Publication
BMC Cancer, 2015, Vol 15, Issue 1, p356
- ISSN
1471-2407
- Publication type
journal article
- DOI
10.1186/s12885-015-1377-8