BRAF inhibition alleviates immune suppression in murine autochthonous melanoma

Cancer Immunol Res. 2014 Nov;2(11):1044-50. doi: 10.1158/2326-6066.CIR-14-0074. Epub 2014 Sep 2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cross-Priming
  • Enzyme Inhibitors / pharmacology
  • Flow Cytometry
  • Indoles / pharmacology*
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Melanoma, Experimental / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Myeloid Cells / drug effects*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Sulfonamides / pharmacology*
  • T-Lymphocytes, Regulatory / drug effects*
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Indoles
  • PLX 4720
  • Sulfonamides
  • Braf protein, mouse
  • Proto-Oncogene Proteins B-raf