title: Host immunity contributes to the anti-melanoma activity of BRAF inhibitors.
abstract: The BRAF mutant, BRAF(V600E), is expressed in nearly half of melanomas, and oral BRAF inhibitors induce substantial tumor regression in patients with BRAF(V600E) metastatic melanoma. The inhibitors are believed to work primarily by inhibiting BRAF(V600E)-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 Braf(V600E)-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 Braf(V600E) 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: Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, Australia.
authors: Deborah A
authors: DA
authors: Knight
authors: Shin Foong
authors: SF
authors: Ngiow
authors: Ming
authors: M
authors: Li
authors: Tiffany
authors: T
authors: Parmenter
authors: Stephen
authors: S
authors: Mok
authors: Ashley
authors: A
authors: Cass
authors: Nicole M
authors: NM
authors: Haynes
authors: Kathryn
authors: K
authors: Kinross
authors: Hideo
authors: H
authors: Yagita
authors: Richard C
authors: RC
authors: Koya
authors: Thomas G
authors: TG
authors: Graeber
authors: Antoni
authors: A
authors: Ribas
authors: Grant A
authors: GA
authors: McArthur
authors: Mark J
authors: MJ
authors: Smyth
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007111:Immunity, Cellular; D007167:Immunotherapy; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D020125:Mutation, Missense; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D054390:Receptors, CCR2 / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D007211:Indoles; C528407:PLX 4720; D054390:Receptors, CCR2; D013449:Sulfonamides; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf