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Proteogenomic Analysis Unveils the HLA Class I-Presented Immunopeptidome in Melanoma and EGFR-Mutant Lung Adenocarcinoma

Immune checkpoint inhibitors and adoptive lymphocyte transfer–based therapies have shown great therapeutic potential in cancers with high tumor mutational burden (TMB), such as melanoma, but not in cancers with low TMB, such as mutant epidermal growth factor receptor (EGFR)–driven lung adenocarcinom...

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Autores principales: Qi, Yue A., Maity, Tapan K., Cultraro, Constance M., Misra, Vikram, Zhang, Xu, Ade, Catherine, Gao, Shaojian, Milewski, David, Nguyen, Khoa D., Ebrahimabadi, Mohammad H., Hanada, Ken-ichi, Khan, Javed, Sahinalp, Cenk, Yang, James C., Guha, Udayan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8724932/
https://www.ncbi.nlm.nih.gov/pubmed/34391887
http://dx.doi.org/10.1016/j.mcpro.2021.100136
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author Qi, Yue A.
Maity, Tapan K.
Cultraro, Constance M.
Misra, Vikram
Zhang, Xu
Ade, Catherine
Gao, Shaojian
Milewski, David
Nguyen, Khoa D.
Ebrahimabadi, Mohammad H.
Hanada, Ken-ichi
Khan, Javed
Sahinalp, Cenk
Yang, James C.
Guha, Udayan
author_facet Qi, Yue A.
Maity, Tapan K.
Cultraro, Constance M.
Misra, Vikram
Zhang, Xu
Ade, Catherine
Gao, Shaojian
Milewski, David
Nguyen, Khoa D.
Ebrahimabadi, Mohammad H.
Hanada, Ken-ichi
Khan, Javed
Sahinalp, Cenk
Yang, James C.
Guha, Udayan
author_sort Qi, Yue A.
collection PubMed
description Immune checkpoint inhibitors and adoptive lymphocyte transfer–based therapies have shown great therapeutic potential in cancers with high tumor mutational burden (TMB), such as melanoma, but not in cancers with low TMB, such as mutant epidermal growth factor receptor (EGFR)–driven lung adenocarcinoma. Precision immunotherapy is an unmet need for most cancers, particularly for cancers that respond inadequately to immune checkpoint inhibitors. Here, we employed large-scale MS-based proteogenomic profiling to identify potential immunogenic human leukocyte antigen (HLA) class I-presented peptides in melanoma and EGFR-mutant lung adenocarcinoma. Similar numbers of peptides were identified from both tumor types. Cell line and patient-specific databases (DBs) were constructed using variants identified from whole-exome sequencing. A de novo search algorithm was used to interrogate the HLA class I immunopeptidome MS data. We identified 12 variant peptides and several classes of tumor-associated antigen-derived peptides. We constructed a cancer germ line (CG) antigen DB with 285 antigens. This allowed us to identify 40 class I-presented CG antigen–derived peptides. The class I immunopeptidome comprised more than 1000 post-translationally modified (PTM) peptides representing 58 different PTMs, underscoring the critical role PTMs may play in HLA binding. Finally, leveraging de novo search algorithm and an annotated long noncoding RNA (lncRNA) DB, we developed a novel lncRNA-encoded peptide discovery pipeline to identify 44 lncRNA-derived peptides that are presented by class I. We validated tandem MS spectra of select variant, CG antigen, and lncRNA-derived peptides using synthetic peptides and performed HLA class I-binding assays to demonstrate binding to class I proteins. In summary, we provide direct evidence of HLA class I presentation of a large number of variant and tumor-associated peptides in both low and high TMB cancer. These results can potentially be useful for precision immunotherapies, such as vaccine or adoptive cell therapies in melanoma and EGFR-mutant lung cancers.
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spelling pubmed-87249322022-01-11 Proteogenomic Analysis Unveils the HLA Class I-Presented Immunopeptidome in Melanoma and EGFR-Mutant Lung Adenocarcinoma Qi, Yue A. Maity, Tapan K. Cultraro, Constance M. Misra, Vikram Zhang, Xu Ade, Catherine Gao, Shaojian Milewski, David Nguyen, Khoa D. Ebrahimabadi, Mohammad H. Hanada, Ken-ichi Khan, Javed Sahinalp, Cenk Yang, James C. Guha, Udayan Mol Cell Proteomics Research Immune checkpoint inhibitors and adoptive lymphocyte transfer–based therapies have shown great therapeutic potential in cancers with high tumor mutational burden (TMB), such as melanoma, but not in cancers with low TMB, such as mutant epidermal growth factor receptor (EGFR)–driven lung adenocarcinoma. Precision immunotherapy is an unmet need for most cancers, particularly for cancers that respond inadequately to immune checkpoint inhibitors. Here, we employed large-scale MS-based proteogenomic profiling to identify potential immunogenic human leukocyte antigen (HLA) class I-presented peptides in melanoma and EGFR-mutant lung adenocarcinoma. Similar numbers of peptides were identified from both tumor types. Cell line and patient-specific databases (DBs) were constructed using variants identified from whole-exome sequencing. A de novo search algorithm was used to interrogate the HLA class I immunopeptidome MS data. We identified 12 variant peptides and several classes of tumor-associated antigen-derived peptides. We constructed a cancer germ line (CG) antigen DB with 285 antigens. This allowed us to identify 40 class I-presented CG antigen–derived peptides. The class I immunopeptidome comprised more than 1000 post-translationally modified (PTM) peptides representing 58 different PTMs, underscoring the critical role PTMs may play in HLA binding. Finally, leveraging de novo search algorithm and an annotated long noncoding RNA (lncRNA) DB, we developed a novel lncRNA-encoded peptide discovery pipeline to identify 44 lncRNA-derived peptides that are presented by class I. We validated tandem MS spectra of select variant, CG antigen, and lncRNA-derived peptides using synthetic peptides and performed HLA class I-binding assays to demonstrate binding to class I proteins. In summary, we provide direct evidence of HLA class I presentation of a large number of variant and tumor-associated peptides in both low and high TMB cancer. These results can potentially be useful for precision immunotherapies, such as vaccine or adoptive cell therapies in melanoma and EGFR-mutant lung cancers. American Society for Biochemistry and Molecular Biology 2021-08-13 /pmc/articles/PMC8724932/ /pubmed/34391887 http://dx.doi.org/10.1016/j.mcpro.2021.100136 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research
Qi, Yue A.
Maity, Tapan K.
Cultraro, Constance M.
Misra, Vikram
Zhang, Xu
Ade, Catherine
Gao, Shaojian
Milewski, David
Nguyen, Khoa D.
Ebrahimabadi, Mohammad H.
Hanada, Ken-ichi
Khan, Javed
Sahinalp, Cenk
Yang, James C.
Guha, Udayan
Proteogenomic Analysis Unveils the HLA Class I-Presented Immunopeptidome in Melanoma and EGFR-Mutant Lung Adenocarcinoma
title Proteogenomic Analysis Unveils the HLA Class I-Presented Immunopeptidome in Melanoma and EGFR-Mutant Lung Adenocarcinoma
title_full Proteogenomic Analysis Unveils the HLA Class I-Presented Immunopeptidome in Melanoma and EGFR-Mutant Lung Adenocarcinoma
title_fullStr Proteogenomic Analysis Unveils the HLA Class I-Presented Immunopeptidome in Melanoma and EGFR-Mutant Lung Adenocarcinoma
title_full_unstemmed Proteogenomic Analysis Unveils the HLA Class I-Presented Immunopeptidome in Melanoma and EGFR-Mutant Lung Adenocarcinoma
title_short Proteogenomic Analysis Unveils the HLA Class I-Presented Immunopeptidome in Melanoma and EGFR-Mutant Lung Adenocarcinoma
title_sort proteogenomic analysis unveils the hla class i-presented immunopeptidome in melanoma and egfr-mutant lung adenocarcinoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8724932/
https://www.ncbi.nlm.nih.gov/pubmed/34391887
http://dx.doi.org/10.1016/j.mcpro.2021.100136
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