title: BRAF inhibition alleviates immune suppression in murine autochthonous melanoma.
abstract: A growing body of evidence suggests that BRAF inhibitors, in addition to their acute tumor growth-inhibitory effects, can also promote immune responses to melanoma. The present study aimed to define the immunologic basis of BRAF-inhibitor therapy using the Braf/Pten model of inducible, autochthonous melanoma on a pure C57BL/6 background. In the tumor microenvironment, BRAF inhibitor PLX4720 functioned by on-target mechanisms to selectively decrease both the proportions and absolute numbers of CD4(+)Foxp3(+) regulatory T cells (Treg) and CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSC), while preserving numbers of CD8(+) effector T cells. In PLX4720-treated mice, the intratumoral Treg populations decreased significantly, demonstrating enhanced apopotosis. CD11b(+) myeloid cells from PLX4720-treated tumors also exhibited decreased immunosuppressive function on a per-cell basis. In accordance with a reversion of tumor immune suppression, tumors that had been treated with PLX4720 grew with reduced kinetics after treatment was discontinued, and this growth delay was dependent on CD8 T cells. These findings demonstrate that BRAF inhibition selectively reverses two major mechanisms of immunosuppression in melanoma and liberates host-adaptive antitumor immunity.
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Peisheng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Malik
authors.affiliation: Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Andrea
authors.initials: A
authors.lastname: Boni
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Tamer B
authors.initials: TB
authors.lastname: Shabaneh
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Katelyn T
authors.initials: KT
authors.lastname: Byrne
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Norris-Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: David W
authors.initials: DW
authors.lastname: Mullins
authors.affiliation: Norris-Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Constance E
authors.initials: CE
authors.lastname: Brinckerhoff
authors.affiliation: Norris-Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Ernstoff
authors.affiliation: Department of Dermatology and Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Bosenberg
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Norris-Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. mary.jo.turk@dartmouth.edu.
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Turk
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045142:Cross-Priming; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D007211:Indoles / Q000494:pharmacology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D022423:Myeloid Cells / Q000187:drug effects*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; C528407:PLX 4720; D013449:Sulfonamides; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf