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Melanoma Res. 2016 Feb;26(1):1-11. doi: 10.1097/CMR.0000000000000203.

Type I-polarized BRAF-pulsed dendritic cells induce antigen-specific CD8+ T cells that impact BRAF-mutant murine melanoma.

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aHarrison Department of Surgical Research, Perelman School of Medicine, University of Pennsylvania bWistar Institute, Philadelphia, Pennsylvania, USA.


Existing therapies targeting the mutated BRAF oncodriver (BRAF(V600E)) successfully treat melanoma but are susceptible to resistance. This study assessed the potential of a dendritic cell-based BRAF(V600E) vaccine for the treatment of BRAF(V600E)-mutant melanoma. Type 1-polarized dendritic cells (DC1) pulsed with affinity-modified BRAF(V600E) peptide were administered to C57Bl/6 mice both before (prevention) and twice weekly after (treatment) the development of established tumor with B16 melanoma transfected to express BRAF(V600E) (B16(V600E)). The efficacy of the BRAF(V600E)-pulsed DC1 vaccine was corroborated in a novel transplantable BRAF(V600E)-mutant murine melanoma model (BRAF(V600E-/+); PTEN(-/-); CDK2NA(-/-)). Three-dimensional tumor measurements and survival were determined. Induction of BRAF(V600E)-specific CD8(+) T-cell responses after brief in-vitro sensitization was assessed by interferon-γ enzyme-linked immunosorbent assay and/or enzyme-linked immunospot. Mice receiving BRAF(V600E)-pulsed DC1 vaccines before B16(V600E) tumor challenge demonstrated increased tumor-doubling times (P<0.001) and improved survival (P=0.0186) compared with those that received ovalbumin (control)-pulsed DC1 vaccines. In mice bearing established B16(V600E) tumors (mean 32 mm(3)), BRAF-pulsed DC1 vaccines delayed tumor growth (P<0.001) and improved survival (P=0.0008), compared with untreated mice. Likewise, in mice bearing BRAF(V600E-/+); PTEN(-/-); CDK2NA(-/-) tumors, compared with controls, BRAF-DC1 vaccination recapitulated these effects by delaying tumor growth (P<0.001) and improving survival (P=0.002). Vaccination elicited specific CD8(+) T-cell recognition of BRAF(V600E)-pulsed antigen-presenting cells (P<0.05), as well as BRAF(V600E)-expressing cancer cells (P<0.001), measured by interferon-γ release in vitro. BRAF-(V600E)pulsed DC1 vaccines induce oncogene-specific CD8(+) T-cell immune responses that impact tumor growth and survival in preclinical models of BRAF(V600E)-mutant melanoma. Exploration of BRAF(V600E)-targeted vaccines, in combination with BRAF-targeted therapies and checkpoint inhibitors, is warranted.

[Indexed for MEDLINE]

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