Host immunity contributes to the anti-melanoma activity of BRAF inhibitors
Deborah A. Knight, … , Grant A. McArthur, Mark J. Smyth
Deborah A. Knight, … , Grant A. McArthur, Mark J. Smyth
Published March 1, 2013; First published February 1, 2013
Citation Information: J Clin Invest. 2013;123(3):1371-1381. https://doi.org/10.1172/JCI66236.
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Research Article

Host immunity contributes to the anti-melanoma activity of BRAF inhibitors

Abstract

The BRAF mutant, BRAFV600E, is expressed in nearly half of melanomas, and oral BRAF inhibitors induce substantial tumor regression in patients with BRAFV600E metastatic melanoma. The inhibitors are believed to work primarily by inhibiting BRAFV600E-induced oncogenic MAPK signaling; however, some patients treated with BRAF inhibitors exhibit increased tumor immune infiltration, suggesting that a combination of BRAF inhibitors and immunotherapy may be beneficial. We used two relatively resistant variants of BrafV600E-driven mouse melanoma (SM1 and SM1WT1) and melanoma-prone mice to determine the role of host immunity in type I BRAF inhibitor PLX4720 antitumor activity. We found that PLX4720 treatment downregulated tumor Ccl2 gene expression and decreased tumor CCL2 expression in both BrafV600E mouse melanoma transplants and in de novo melanomas in a manner that was coincident with reduced tumor growth. While PLX4720 did not directly increase tumor immunogenicity, analysis of SM1 tumor-infiltrating leukocytes in PLX4720-treated mice demonstrated a robust increase in CD8+ T/FoxP3+CD4+ T cell ratio and NK cells. Combination therapy with PLX4720 and anti-CCL2 or agonistic anti-CD137 antibodies demonstrated significant antitumor activity in mouse transplant and de novo tumorigenesis models. These data elucidate a role for host CCR2 in the mechanism of action of type I BRAF inhibitors and support the therapeutic potential of combining BRAF inhibitors with immunotherapy.

Authors

Deborah A. Knight, Shin Foong Ngiow, Ming Li, Tiffany Parmenter, Stephen Mok, Ashley Cass, Nicole M. Haynes, Kathryn Kinross, Hideo Yagita, Richard C. Koya, Thomas G. Graeber, Antoni Ribas, Grant A. McArthur, Mark J. Smyth

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Figure 3

PLX4720 antitumor activity is host CCR2 dependent.

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PLX4720 antitumor activity is host CCR2 dependent. (A) Groups of 5 WT, C...
(A) Groups of 5 WT, Ccl2–/–, or Ccr2–/– mice were inoculated with 5 × 105 SM1WT1 cells. Mice received vehicle or PLX4720 (20 mg/kg i.p.) daily from day 3 to 10 after tumor inoculation. (B and C) Groups of 5 WT or Ccl2–/– mice were inoculated with 5 × 105 SM1WT1 cells. Mice received vehicle or PLX4720 (20 mg/kg i.p.) daily from day 3 to 10 after tumor inoculation. Some groups of mice additionally received cIg or anti-CCL2 mAb (20 μg i.p.) on days 2, 3, 10, 17, and 24. Tumor sizes are represented as the mean ± SEM. Statistical differences in tumor sizes between mice treated with vehicle or PLX4720 therapy were determined by a Mann-Whitney test (*P < 0.05). (A–C) Data are representative of 2 independent experiments.