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Combined presentation and immunogenicity analysis reveals a recurrent RAS.Q61K neoantigen in melanoma
Aviyah Peri, … , Nir Friedman, Yardena Samuels
Aviyah Peri, … , Nir Friedman, Yardena Samuels
Published October 15, 2021
Citation Information: J Clin Invest. 2021;131(20):e129466. https://doi.org/10.1172/JCI129466.
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Research Article Genetics Oncology Article has an altmetric score of 49

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

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Abstract

Neoantigens are now recognized drivers of the antitumor immune response. Recurrent neoantigens, shared among groups of patients, have thus become increasingly coveted therapeutic targets. Here, we report on the data-driven identification of a robustly presented, immunogenic neoantigen that is derived from the combination of HLA-A*01:01 and RAS.Q61K. Analysis of large patient cohorts indicated that this combination applies to 3% of patients with melanoma. Using HLA peptidomics, we were able to demonstrate robust endogenous presentation of the neoantigen in 10 tumor samples. We detected specific reactivity to the mutated peptide within tumor-infiltrating lymphocytes (TILs) from 2 unrelated patients, thus confirming its natural immunogenicity. We further investigated the neoantigen-specific clones and their T cell receptors (TCRs) via a combination of TCR sequencing, TCR overexpression, functional assays, and single-cell transcriptomics. Our analysis revealed a diverse repertoire of neoantigen-specific clones with both intra- and interpatient TCR similarities. Moreover, 1 dominant clone proved to cross-react with the highly prevalent RAS.Q61R variant. Transcriptome analysis revealed a high association of TCR clones with specific T cell phenotypes in response to cognate melanoma, with neoantigen-specific cells showing an activated and dysfunctional phenotype. Identification of recurrent neoantigens and their reactive TCRs can promote “off-the-shelf” precision immunotherapies, alleviating limitations of personalized treatments.

Authors

Aviyah Peri, Erez Greenstein, Michal Alon, Joy A. Pai, Tamir Dingjan, Shlomit Reich-Zeliger, Eilon Barnea, Chaya Barbolin, Ronen Levy, Claudia Arnedo-Pac, Shelly Kalaora, Bareket Dassa, Ester Feldmesser, Ping Shang, Polina Greenberg, Yishai Levin, Gil Benedek, Mitchell P. Levesque, David J. Adams, Michal Lotem, James S. Wilmott, Richard A. Scolyer, Göran B. Jönsson, Arie Admon, Steven A. Rosenberg, Cyrille J. Cohen, Masha Y. Niv, Nuria Lopez-Bigas, Ansuman T. Satpathy, Nir Friedman, Yardena Samuels

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Figure 5

N135.1 TCR similarity cluster within 17TIL converges on both α and β chains.

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N135.1 TCR similarity cluster within 17TIL converges on both α and β cha...
Inspection of the 17TIL repertoire revealed a cluster of 4 TCRs that were similar to N135.1: N17.3.2, N17.5, N17.6, and N17.7. The top most frequent TCRs on this list, N17.3.2 and N17.5, were validated as potent and neoantigen specific (see Figures 6 and 7). (A) Both α and β chains for the similarity cluster were enriched in the tetramer+ subpopulation. α/β Pairings were confirmed by single-cell TCR sequencing. Representative data (replicate 1 of 3) from bulk TCR sequencing. (B) Sequence comparison of the TCRs’ variable regions. Note the Hamming distance of up to 4 amino acids and the similarity of the V/J genes. (C) TCRs were plotted according to the Pgen of their α (x axis) and β chains (y axis). NH1 (NRAS hybrid TCR no. 1) combines the most probable α/β within the similarity cluster; it was generated through chain swapping between N135.1 and N17.5. NH2 is the counterpart to NH1, mixing NA17.5 with NB135.1. (D) Illustration of the chain swapping generating NH1, combining NA135.1 with NB17.5.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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