Combined Presentation and Immunogenicity Analysis Reveals Recurrence of RAS.Q61K Neoplastic Antigen in Melanoma

Citation Information: J Clin Invest. 2021;131(20):e129466. https://doi.org/10.1172/JCI129466.

Commentary

Since neoantigens are now recognized as drivers of anti-tumor immune responses, recurrent neoantigens shared among groups of patients have become a much-needed therapeutic target.

In this study, we report the data-driven identification of robustly presented immunogenic neoantigens derived from the combination of HLA-A * 01:01 and RAS.Q61K.

Analysis of a large patient cohort showed that this combination is applicable to 3% of melanoma patients.

Using HLA peptidomics, we were able to demonstrate a strong endogenous presentation of the neoantigen in 10 tumor samples.

We detected specific reactivity to the mutant peptide within tumor infiltrating lymphocytes (TILs) from two unrelated patients, confirming its natural immunogenicity.

We further investigated neoantigen-specific clones and their T-cell receptors (TCRs) via a combination of TCR sequencing, TCR overexpression, functional assays, and single-cell transcriptomics.

The investigative analysis revealed a diverse repertoire of neoantigen-specific clones with both intra- and inter-patient TCR similarities, and demonstrated that one dominant clone cross-reacted with the highly prevalent RAS.Q61R variant.

Transcriptome analysis revealed a high degree of association between the TCR clone and a specific T cell phenotype in response to homologous melanoma, with neoplastic antigen-specific cells exhibiting an activated and dysfunctional phenotype.

The identification of recurrent neoantigens and their reactive TCRs can facilitate "off-the-shelf" precision immunotherapy and alleviate the limitations of personalized therapy.