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

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Abstract

Existing therapies targeting the mutated BRAF oncodriver (BRAFV600E) successfully treat melanoma but are susceptible to resistance. This study assessed the potential of a dendritic cell-based BRAFV600E vaccine for the treatment of BRAFV600E-mutant melanoma. Type 1-polarized dendritic cells (DC1) pulsed with affinity-modified BRAFV600E 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 BRAFV600E (B16V600E). The efficacy of the BRAFV600E-pulsed DC1 vaccine was corroborated in a novel transplantable BRAFV600E-mutant murine melanoma model (BRAFV600E/+; PTEN−/−; CDK2NA−/−). Three-dimensional tumor measurements and survival were determined. Induction of BRAFV600E-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 BRAFV600E-pulsed DC1 vaccines before B16V600E 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 B16V600E tumors (mean 32 mm3), BRAF-pulsed DC1 vaccines delayed tumor growth (P<0.001) and improved survival (P=0.0008), compared with untreated mice. Likewise, in mice bearing BRAFV600E/+; 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 BRAFV600E-pulsed antigen-presenting cells (P<0.05), as well as BRAFV600E-expressing cancer cells (P<0.001), measured by interferon-γ release in vitro. BRAFV600E-pulsed DC1 vaccines induce oncogene-specific CD8+ T-cell immune responses that impact tumor growth and survival in preclinical models of BRAFV600E-mutant melanoma. Exploration of BRAFV600E-targeted vaccines, in combination with BRAF-targeted therapies and checkpoint inhibitors, is warranted.

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