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 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 8

Combination antitumor activity of PLX4720/anti-CD137 against de novo BRAFV600E-driven mouse melanomas.

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Combination antitumor activity of PLX4720/anti-CD137 against de novo BRA...
Groups of BrafV600E transgenic mice (n = 6–7) were induced for localized melanoma by 4-HT application on day 0. Mice received vehicle or PLX4720 (20 mg/kg i.p.) daily from day 28 to 49. Some groups of mice additionally received cIg or anti-CD137 (100 μg i.p.) on days 28, 32, 36, 40, 44, and 48. (A) At the indicated time, tumor sizes (height; mm) were recorded and represented as the mean ± SEM. Statistical differences in tumor sizes between different groups of mice were determined by a Mann-Whitney test (**P < 0.01; #P < 0.0001). (B) At day 49, tumors were excised and weighed. Statistical differences in tumor weights between different groups of mice were determined by a Mann-Whitney test (*P < 0.05, PLX4720 and clg compared with vehicle and anti-CD137; #P < 0.001, vehicle and clg compared with PLX4720 and clg [P = 0.0004] or PLX4720 and anti-CD137 [P = 0.0001] and vehicle and anti-CD137 compared with PLX4720 and anti-CD137 [P = 0.0008]). Data shown are pooled from 2 independent experiments. Individual symbols represent individual tumors; horizontal bars indicate the mean.