Combined presentation and immunogenicity analysis reveals a recurrent RAS.Q61K neoantigen in melanoma

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Neoantigens are key drivers of the antitumor immune response.
• Recurrent neoantigens, shared across patient groups, are valuable therapeutic targets.

Purpose of the Study:

• To identify and characterize a robustly presented, immunogenic neoantigen derived from HLA-A*01:01 and RAS.Q61K.
• To investigate the T cell receptor (TCR) repertoire and phenotypes associated with this neoantigen in melanoma.

Main Methods:

• HLA peptidomics to detect endogenous neoantigen presentation.
• TCR sequencing, overexpression, functional assays, and single-cell transcriptomics.
• Analysis of large patient cohorts and tumor-infiltrating lymphocytes (TILs).

Main Results:

• Identification of a shared neoantigen (RAS.Q61K) presented by HLA-A*01:01 in 3% of melanoma patients.
• Demonstration of endogenous neoantigen presentation and specific TIL reactivity.
• Characterization of diverse neoantigen-specific T cell clones, including one cross-reactive to RAS.Q61R.
• Association of TCR clones with activated, dysfunctional T cell phenotypes in melanoma.

Conclusions:

• The identified recurrent neoantigen is immunogenic and presents therapeutic potential.
• Understanding neoantigen-specific T cell responses informs precision immunotherapy development.
• Discovery facilitates the creation of "off-the-shelf" immunotherapies, overcoming personalized treatment limitations.