Dataset Information

HLA class I-restricted T cell epitopes isolated and identified from myeloid leukemia cells.

ABSTRACT: Leukemia-associated antigens (LAAs) and HLA-I epitopes published previously have shown promise in inducing leukemia-specific T cell responses. However, the clinical responses are limited, and clinical effectiveness is yet to be achieved. Limitations, among others, being the LAAs themselves, the indirect approach to HLA-I epitope identification by reverse immunology, and the use of single or few LAAs and HLA-I epitopes, which limits the spectrum of inducible tumor-specific T cells. Use of a direct approach to identify naturally processed and presented HLA-I epitopes from LAAs, and higher numbers of antigens for T cell-mediated immunotherapy for leukemia may enhance clinical responses and broaden clinical effectiveness. In a prior study we used immunoaffinity purification of HLA-I peptide complexes from the differentiated myeloid tumor cell lines MUTZ3 and THP1 coupled to high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS). From this we identified in the current study seven new HLA-I epitopes and the corresponding LAAs for myeloid leukemia. In comparison, the myeloid HLA-I epitopes reported here were generally stronger HLA-binders that induce stronger T cell responses than those previously published, and their source LAAs had higher immunogenicity, higher expression levels in myeloid tumors cells compared to normal hemopoietin and other major normal tissues, and more protein interaction partners, and they are targeted by CD8 T cells in CML patients. This study analyses and compares the LAAs and HLA-I epitopes based on various immunotherapeutic targets selection criteria, and highlights new targets for T cell-mediated immunotherapy for leukemia.

SUBMITTER: Nyambura LW

PROVIDER: S-EPMC6773711 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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HLA class I-restricted T cell epitopes isolated and identified from myeloid leukemia cells.

Nyambura Lydon Wainaina LW Muñoz Alejandro Azorin AA le Coutre Philipp P Walden Peter P

Scientific reports 20191001 1

Leukemia-associated antigens (LAAs) and HLA-I epitopes published previously have shown promise in inducing leukemia-specific T cell responses. However, the clinical responses are limited, and clinical effectiveness is yet to be achieved. Limitations, among others, being the LAAs themselves, the indirect approach to HLA-I epitope identification by reverse immunology, and the use of single or few LAAs and HLA-I epitopes, which limits the spectrum of inducible tumor-specific T cells. Use of a direc ...[more]

PMID: 31575892

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Project description:BACKGROUND: All four dengue virus (DV) serotypes (D1V, D2V, D3V and D4V) can cause a series of disorders, ranging from mild dengue fever (DF) to severe dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). Previous studies have revealed that DV serotype-specific CD8(+) T cells are involved in controlling DV infection. Serotype cross-reactive CD8(+) T-cells may contribute to the immunopathogenesis of DHF/DSS. The aim of the study was to identify HLA-A*0201-binding peptides from four DV serotypes. We then examined their immunogenicity in vivo and cross-reactivity within heterologous peptides. METHODS: D1V-derived candidate CD8(+) T-cell epitopes were synthesized and evaluated for their affinity to the HLA-A*0201 molecule. Variant peptides representing heterologous D2V, D3V, D4V serotypes were synthesized. The immunogenicity of the high-affinity peptides were evaluated in HLA-A*0201 transgenic mice. RESULTS: Of the seven D1V-derived candidate epitopes [D1V-NS4a(56-64)(MLLALIAVL), D1V-C(46-54)(LVMAFMAFL), D1V-NS4b(562-570)(LLATSIFKL), D1V-NS2a(169-177)(AMVLSIVSL), D1V-NS4a(140-148)(GLLFMILTV), D1V-NS2a(144-152)(QLWAALLSL) and D1V-NS4b(183-191)(LLMRTTWAL)], three peptides [D1V-NS4a(140-148), D1V-NS2a(144-152) and D1V-NS4b(183-191)] had a high affinity for HLA-A*0201 molecules. Moreover, their variant peptides for D2V, D3V and D4V [D2V-NS4a(140-148)(AILTVVAAT), D3V-NS4a(140-148)(GILTLAAIV), D4V-NS4a(140-148)(TILTIIGLI), D2V-NS2a(144-152)(QLAVTIMAI), D3V-NS2a(144-152)(QLWTALVSL), D4V-NS2a(143-151)(QVGTLALSL), D2V-NS4b(182-190)(LMMRTTWAL), D3V-NS4b(182-190) (LLMRTSWAL) and D4V-NS4b(179-187)(LLMRTTWAF)] also had a high affinity for HLA-A*0201 molecules. Furthermore, CD8+ T cells directed to these twelve peptides were induced in HLA-A*0201 transgenic mice following immunization with these peptides. Additionally, cross-reactivity within four peptides (D1V-NS4b(183-191), D2V-NS4b(182-190), D3V-NS4b(182-190) and D4V-NS4b(179-187)) was observed. CONCLUSIONS: Two novel serotype-specific HLA-A*0201-restricted CD8(+) T-cell epitopes (NS4a(140-148) and NS2a(144-152)) and one cross-reactive HLA-A*0201-restricted CD8(+) T-cell epitopes which is similar to a previously identified epitope were identified in D1V-D4V. Combining prediction algorithms and HLA transgenic mice is an effective strategy to identify HLA-restricted epitopes. Serotype-specific epitopes would be used to determine the protective role of serotype-specific CD8(+) T cells, while cross-reactive epitopes may provide assistance in exploring the role of serotype cross-reactive CD8(+) T cells in the immunopathogenesis of DHF/DSS.

Dataset Information

HLA class I-restricted T cell epitopes isolated and identified from myeloid leukemia cells.

Publications

HLA class I-restricted T cell epitopes isolated and identified from myeloid leukemia cells.

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