title: Type I-polarized BRAF-pulsed dendritic cells induce antigen-specific CD8+ T cells that impact BRAF-mutant murine melanoma.
abstract: 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.
authors.affiliation: aHarrison Department of Surgical Research, Perelman School of Medicine, University of Pennsylvania bWistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Cintolo
authors.forename: Jashodeep
authors.initials: J
authors.lastname: Datta
authors.forename: Shuwen
authors.initials: S
authors.lastname: Xu
authors.forename: Meera
authors.initials: M
authors.lastname: Gupta
authors.forename: Rajasekharan
authors.initials: R
authors.lastname: Somasundaram
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Czerniecki
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020125:Mutation, Missense; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy
chemical_list: D019496:Cancer Vaccines; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf