Combined presentation and immunogenicity analysis reveals a recurrent RAS.Q61K neoantigen in melanoma
(2021) In Journal of Clinical Investigation 131(20).- 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... (More)
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-theshelf" precision immunotherapies, alleviating limitations of personalized treatments.
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- author
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Clinical Investigation
- volume
- 131
- issue
- 20
- article number
- e129466
- publisher
- The American Society for Clinical Investigation
- external identifiers
-
- scopus:85118254192
- pmid:34651586
- ISSN
- 0021-9738
- DOI
- 10.1172/JCI129466
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2021 American Society for Clinical Investigation. All rights reserved.
- id
- 1bb02bae-0f47-4cbb-a991-10bb1b6f9b4b
- date added to LUP
- 2021-11-24 13:59:38
- date last changed
- 2024-06-15 21:28:09
@article{1bb02bae-0f47-4cbb-a991-10bb1b6f9b4b,
abstract = {{<p>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-theshelf" precision immunotherapies, alleviating limitations of personalized treatments.</p>}},
author = {{Peri, Aviyah and Greenstein, Erez and Alon, Michal and Pai, Joy A. and Dingjan, Tamir and Reich-Zeliger, Shlomit and Barnea, Eilon and Barbolin, Chaya and Levy, Ronen and Arnedo-Pac, Claudia and Kalaora, Shelly and Dassa, Bareket and Feldmesser, Ester and Shang, Ping and Greenberg, Polina and Levin, Yishai and Benedek, Gil and Levesque, Mitchell P. and Adams, David J. and Lotem, Michal and Wilmott, James S. and Scolyer, Richard A. and Jönsson, Göran B. and Admon, Arie and Rosenberg, Steven A. and Cohen, Cyrille J. and Niv, Masha Y. and Lopez-Bigas, Nuria and Satpathy, Ansuman T. and Friedman, Nir and Samuels, Yardena}},
issn = {{0021-9738}},
language = {{eng}},
number = {{20}},
publisher = {{The American Society for Clinical Investigation}},
series = {{Journal of Clinical Investigation}},
title = {{Combined presentation and immunogenicity analysis reveals a recurrent RAS.Q61K neoantigen in melanoma}},
url = {{http://dx.doi.org/10.1172/JCI129466}},
doi = {{10.1172/JCI129466}},
volume = {{131}},
year = {{2021}},
}