Dataset Information

Proteogenomic analysis unveils the expression of cancer associated and specific antigen-derived HLA Class ǀ immunopeptides in melanoma and EGFR mutant lung adenocarcinoma

ABSTRACT: Immunotherapy has shown great therapeutic potential for cancers with high tumor mutational burden (TMB), but much less promise for cancers with low TMB. One primary approach for adoptive lymphocyte transfer-based immunotherapy is to target the somatic mutated peptide neoantigens and cancer testis (CT) antigens recognized by cytotoxic T cells. Here, we employed mass spectrometry (MS)-based proteogenomic large-scale profiling to identify potential immunogenic human leukocyte antigen (HLA) Class ǀ- associated peptides in both melanoma, a “hot tumor”, and EGFR mutant lung adenocarcinoma, a “cold tumor”. We uncovered 19 common driver oncogene-derived peptides and more than 1000 post-translationally modified peptides (PTM) representing 58 different PTMs. We constructed a CT antigen database with 286 antigens by compiling reputed CT antigen resources and “in-house” genomic data and used this to identify 45 CT antigen-derived peptides from the identified HLA peptidome. Using integrated next generation sequencing data, we discovered 12 neopeptides in EGFR mutant lung cancer cell lines. Finally, we report a novel approach for non-canonical peptide discovery, whereby we leveraged a deep learning-based de novo search and a high confidence annotated long noncoding RNA (LncRNA) database to identify 44 lncRNA-derived peptides. Findings of this study, for the first time, provide evidence for a large pool of actionable cancer antigen-derived peptides for use in mutant EGFR lung cancer immunotherapy.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Primary Cell, Lung, Epithelial Cell

DISEASE(S): Lung Adenocarcinoma,Melanoma

SUBMITTER: Yue Andy Qi

LAB HEAD: Udayan Guha

PROVIDER: PXD019774 | Pride | 2021-12-07

REPOSITORIES: Pride

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Publications

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

Qi Yue A YA Maity Tapan K TK Cultraro Constance M CM Misra Vikram V Zhang Xu X Ade Catherine C Gao Shaojian S Milewski David D Nguyen Khoa D KD Ebrahimabadi Mohammad H MH Hanada Ken-Ichi KI Khan Javed J Sahinalp Cenk C Yang James C JC Guha Udayan U

Molecular & cellular proteomics : MCP 20210813

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 p ...[more]

PMID: 34391887

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Project description:Background Clinical success of T cell receptor (TCR) gene therapy has previously been demonstrated for NY-ESO-1 TCR gene therapy. To increase numbers of cancer patients that can be treated with TCR gene therapy we aimed to identify a novel set of high-affinity cancer specific TCRs targeting different cancer testis (CT) antigens in prevalent HLA class I alleles. Methods In this study, we selected based on publicly available gene expression databases the most promising CT genes to target. From these selected genes we identified by HLA peptidomics the naturally processed and presented HLA class I peptides. With these peptide-HLA tetramers were generated, and by single cell sorting CT specific CD8+ T cells were selected, and expanded from the allo-HLA repertoire of healthy donors. By several functional assays high avidity CT-specific T cell clones with safe recognition pattern were selected. To evaluate the potential for clinical application in TCR gene therapy, TCRs were sequenced and transferred into peripheral blood derived CD8+ T cells. Results In total we identified, 7 novel CT-specific TCRs that effectively target MAGE-A1, MAGE-A3, MAGE-A6 and MAGE-A9 in the context of human leukocyte antigen(HLA) -A1, -A2, -A3, -B7, -B35 and -C7. TCR gene transfer into CD8⁺ T cells resulted in efficient cytokine production and cytotoxicity of variety of different tumor types without detectable cross-reactivity. In addition, major in vivo antitumor effects of MAGE-A1 specific TCR engineered CD8⁺ T cells was observed in an orthotopic xenograft model for established multiple myeloma, in which bone marrow located tumor cells were completely eradicated after T cell injection. Conclusion The identification of 7 novel CT-specific TCRs, reactive against CT antigens presented in a variety of different HLA class I alleles, allows selection of therapeutic TCRs for an increased number of cancer patients, and will improve development of personalized TCR gene therapy.

Dataset Information

Proteogenomic analysis unveils the expression of cancer associated and specific antigen-derived HLA Class ǀ immunopeptides in melanoma and EGFR mutant lung adenocarcinoma

Publications

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

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