Immunogenicity of constitutively active V599EBRaf.

Area of Science:

• Immunology
• Oncology
• Genetics

Background:

• Activating BRAF mutations, particularly the V600E variant, are common drivers in melanoma.
• The immune system's role in recognizing and eliminating cancer cells with specific mutations is crucial for tumor control.

Purpose of the Study:

• To investigate the existence and specificity of T-cell responses against the BRAF V600E mutation in melanoma patients.
• To explore the potential impact of these mutation-specific T-cell responses on melanoma progression and immune evasion.

Main Methods:

• Analysis of T-cell responses in melanoma patients.
• Epitope mapping and T-cell recognition assays using mutated (V600E)BRAF and wild-type BRAF peptides.
• Correlation of T-cell responses with melanoma genotype during disease progression.

Main Results:

• Demonstrated spontaneous HLA-B*2705-restricted cytotoxic T-cell responses specifically targeting an epitope derived from the BRAF V600E mutation.
• Confirmed that these T-cell responses did not recognize the corresponding epitope from wild-type BRAF, indicating high specificity.
• Observed a loss of the BRAF V600E mutation in metastatic melanoma from patients who exhibited specific T-cell responses against this mutation.

Conclusions:

• Melanoma patients can mount specific T-cell immune responses against the common BRAF V600E mutation.
• The presence of these BRAF V600E-specific T-cell responses correlates with immune selection against mutated melanoma clones.
• This suggests an active immune pressure contributing to the emergence of non-mutated melanoma cells during disease progression.