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

Alterations in HLA Class I-Presented Immunopeptidome and Class I-Interactome upon Osimertinib Resistance in EGFR Mutant Lung Adenocarcinoma

Cancers ◽

10.3390/cancers13194977 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4977

Author(s):

Yue A. Qi ◽

Tapan K. Maity ◽

Shaojian Gao ◽

Tao Gong ◽

Meriam Bahta ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Antigen Presentation ◽

Molecular Mechanisms ◽

Isotope Labeling ◽

Immune Escape ◽

Hla Class I ◽

Class I ◽

Adenocarcinoma Cells ◽

Lung Adenocarcinoma Cells ◽

Egfr Mutant

Immune checkpoint inhibitor (ICI) therapy has been a paradigm shift in the treatment of cancer. ICI therapy results in durable responses and survival benefit for a large number of tumor types. Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has shown great efficacy treating EGFR mutant lung cancers; however, all patients eventually develop resistance. ICI therapy has not benefitted EGFR mutant lung cancer. Herein, we employed stable isotope labeling by amino acids in cell culture (SILAC) quantitative mass spectrometry-based proteomics to investigate potential immune escape molecular mechanisms in osimertinib resistant EGFR mutant lung adenocarcinoma by interrogating the alterations in the human leukocyte antigen (HLA) Class I-presented immunopeptidome, Class I-interactome, and the whole cell proteome between isogenic osimertinib-sensitive and -resistant human lung adenocarcinoma cells. Our study demonstrates an overall reduction in HLA class I-presented immunopeptidome and downregulation of antigen presentation core complex (e.g., TAP1 and ERAP1/2) and immunoproteasome in osimertinib resistant lung adenocarcinoma cells. Several key components in autophagy pathway are differentially altered. S100 proteins and SLC3A2 may play critical roles in reduced antigen presentation. Our dataset also includes ~1000 novel HLA class I interaction partners and hundreds of Class I-presented immunopeptides in EGFR mutant lung adenocarcinoma. This large-scale unbiased proteomics study provides novel insights and potential mechanisms of immune evasion of EGFR mutant lung adenocarcinoma.

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Proteogenomic analysis unveils the HLA Class I-presented immunopeptidome in melanoma and EGFR-mutant lung adenocarcinoma

Molecular & Cellular Proteomics ◽

10.1016/j.mcpro.2021.100136 ◽

2021 ◽

pp. 100136

Author(s):

Yue A. Qi ◽

Tapan K. Maity ◽

Constance M. Cultraro ◽

Vikram Misra ◽

Xu Zhang ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Hla Class I ◽

Class I ◽

Egfr Mutant

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Proteogenomic analysis unveils the HLA Class I presented immunopeptidome in melanoma and EGFR mutant lung adenocarcinoma

10.1101/2020.08.04.236331 ◽

2020 ◽

Cited By ~ 1

Author(s):

Yue A. Qi ◽

Tapan K. Maity ◽

Constance M. Cultraro ◽

Vikram Misra ◽

Xu Zhang ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Large Scale ◽

Therapeutic Potential ◽

Adoptive Cell Therapy ◽

Human Leukocyte ◽

Hla Class I ◽

Class I ◽

Modified Peptides ◽

Lymphocyte Transfer ◽

Egfr Mutant

AbstractImmune checkpoint inhibitor and adoptive lymphocyte transfer-based therapies have shown great therapeutic potential for cancers with high tumor mutation burden (TMB). Here, we employed mass spectrometry (MS)-based proteogenomic large-scale profiling to identify potential immunogenic human leukocyte antigen (HLA) Class I-presented peptides in both melanoma, a “hot tumor” with high TMB, and EGFR mutant lung adenocarcinoma, a “cold tumor” with low TMB. We identified several classes of neopeptides, including mutated neoantigens and more than 1000 post-translationally modified peptides representing 58 different PTMs. We constructed a cancer germline (CG) antigen database with 285 antigens and identified 42 Class I-presented CG antigens. Finally, we developed a non-canonical peptide discovery pipeline to identify 44 lncRNA-derived peptides and validated Class I binding for select neopeptides. We provide direct evidence of HLA Class I presentation of a large number of neopeptides for potential vaccine or adoptive cell therapy in melanoma and mutant EGFR lung cancer.

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Prognostic impact of PD-L1 expression in correlation with HLA class I expression status in stage I adenocarcinoma of the lung.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.8548 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 8548-8548

Author(s):

Kazue Yoneda ◽

Ayako Hirai ◽

Shohei Shimajiri ◽

Takeshi Hanagiri ◽

Fumihiro Tanaka

Keyword(s):

Lung Adenocarcinoma ◽

Early Stage ◽

Human Leukocyte ◽

Hla Class I ◽

Stage I ◽

Class I ◽

Prognostic Impact ◽

Leukocyte Antigen ◽

Molecular Features ◽

Poorly Differentiated

8548 Background: Programmed death-ligand 1 (PD-L1) and human leukocyte antigen (HLA) class-I, expressed on tumor cells (TCs), are important regulators in cancer immunity. The current study was conducted to assess prognostic impact of PD-L1 status in correlation with HLA class-I status in lung adenocarcinoma. Methods: A total of 94 patients with completely resected pathologic stage I lung adenocarcinoma were retrospectively reviewed. PD-L1 expression on TCs was evaluated with immunohistochemistry, in correlation with several clinicopathological and molecular features including HLA class-I expression on tumor TCs. Results: Seventeen patients (18.1%) had tumor with positive PD-L1 expression (percentage of TCs expressing PD-L1, ≥ 5%), and the incidence was higher in smokers with higher smoking index and in poorly differentiated tumor. There was no significant correlation between HLA class-I expression and PD-L1 expression. PD-L1-positivity was a significant factor to predict a poor survival (5-year survival rate, 66.7% versus 85.9%; P = 0.048), which was enhanced in tumor with normal HLA class-I expression (p = 0.029) but disappeared in tumor with reduced HLA class-I expression. Conclusions: The prognostic impact of PD-L1 expression on TCs in early-stage resectable lung adenocarcinoma was distinct according to HLA class-I expression on TCs.

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