PMID- 34391887 OWN - NLM STAT- MEDLINE DCOM- 20220324 LR - 20220324 IS - 1535-9484 (Electronic) IS - 1535-9476 (Print) IS - 1535-9476 (Linking) VI - 20 DP - 2021 TI - Proteogenomic Analysis Unveils the HLA Class I-Presented Immunopeptidome in Melanoma and EGFR-Mutant Lung Adenocarcinoma. PG - 100136 LID - S1535-9476(21)00108-0 [pii] LID - 10.1016/j.mcpro.2021.100136 [doi] LID - 100136 AB - 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. CI - Published by Elsevier Inc. FAU - Qi, Yue A AU - Qi YA AD - Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA. Electronic address: andy.qi@nih.gov. FAU - Maity, Tapan K AU - Maity TK AD - Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA. FAU - Cultraro, Constance M AU - Cultraro CM AD - Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA. FAU - Misra, Vikram AU - Misra V AD - Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA. FAU - Zhang, Xu AU - Zhang X AD - Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA. FAU - Ade, Catherine AU - Ade C AD - Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA. FAU - Gao, Shaojian AU - Gao S AD - Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA. FAU - Milewski, David AU - Milewski D AD - Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA. FAU - Nguyen, Khoa D AU - Nguyen KD AD - Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA. FAU - Ebrahimabadi, Mohammad H AU - Ebrahimabadi MH AD - Cancer Data Science Laboratory, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA; Department of Computer Science, Indiana University, Bloomington, Indiana, USA. FAU - Hanada, Ken-Ichi AU - Hanada KI AD - Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA. FAU - Khan, Javed AU - Khan J AD - Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA. FAU - Sahinalp, Cenk AU - Sahinalp C AD - Cancer Data Science Laboratory, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA. FAU - Yang, James C AU - Yang JC AD - Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA. FAU - Guha, Udayan AU - Guha U AD - Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA; Bristol-Myers Squibb, Lawrenceville, New Jersey, USA. Electronic address: udayan.guha@nih.gov. LA - eng PT - Journal Article PT - Research Support, N.I.H., Intramural DEP - 20210813 PL - United States TA - Mol Cell Proteomics JT - Molecular & cellular proteomics : MCP JID - 101125647 RN - 0 (Antigens, Neoplasm) RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Peptides) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Adenocarcinoma of Lung/genetics/*metabolism MH - Aged MH - Antigens, Neoplasm/genetics/*metabolism MH - Cell Line, Tumor MH - ErbB Receptors/genetics MH - Histocompatibility Antigens Class I/genetics/*metabolism MH - Humans MH - Lung Neoplasms/genetics/*metabolism MH - Male MH - Melanoma/genetics/*metabolism MH - Mutation MH - Peptides/genetics/*metabolism MH - Proteogenomics PMC - PMC8724932 OTO - NOTNLM OT - HLA immunopeptidome OT - immunotherapy OT - lung cancer OT - melanoma OT - neoantigen COIS- Conflict of interest U. G. has a clinical trial agreement with AstraZeneca and had received research funding from AstraZeneca, Aurigene, and Esanex. U. G. is currently an employee of Bristol-Myers Squibb. The other authors declare no competing interests. EDAT- 2021/08/16 06:00 MHDA- 2022/03/25 06:00 PMCR- 2021/08/13 CRDT- 2021/08/15 20:39 PHST- 2020/12/16 00:00 [received] PHST- 2021/08/03 00:00 [revised] PHST- 2021/08/09 00:00 [accepted] PHST- 2021/08/16 06:00 [pubmed] PHST- 2022/03/25 06:00 [medline] PHST- 2021/08/15 20:39 [entrez] PHST- 2021/08/13 00:00 [pmc-release] AID - S1535-9476(21)00108-0 [pii] AID - 100136 [pii] AID - 10.1016/j.mcpro.2021.100136 [doi] PST - ppublish SO - Mol Cell Proteomics. 2021;20:100136. doi: 10.1016/j.mcpro.2021.100136. Epub 2021 Aug 13.