Identification of a novel HLA-A*02:01-restricted cytotoxic T lymphocyte epitope derived from the EML4-ALK fusion gene

Abstract

Cancer immunotherapy is a promising new approach to cancer treatment. It has been demonstrated that a high number of tumor-specific cytotoxic T cells (CTLs) is associated with increased disease-specific survival in lung cancer patients. Identification of superior CTL epitopes from tumor antigens is essential for the development of immunotherapy for malignant tumors. The EML4-ALK fusion gene was recently identified in a subset of non-small cell lung cancers (NSCLCs). In this study we searched for HLA-A*02:01- and HLA-A*24:02-restricted epitopes derived from EML4-ALK by screening predicted EML4-ALK-derived candidate peptides for the induction of tumor-reactive CTLs. Nine EML4-ALK-derived peptides were selected by a computer algorithm based on a permissive HLA-A*02:01 or HLA-A*24:02 binding motif. One of the nine peptides induced peptide-specific CTLs from human peripheral blood mononuclear cells. We were able to generate a peptide-specific CTL clone. This CTL clone specifically recognized peptide-pulsed T2 cells and H2228 cells expressing HLA-A*02:01 and EML4-ALK that had been treated with IFN-γ 48 h prior to examination. CTL activity was inhibited by an anti-HLA-class I monoclonal antibody (W6/32), consistent with a class I-restricted mechanism of cytotoxicity. These results suggest that this peptide (RLSALESRV) is a novel HLA-A*02:01-restricted CTL epitope and that it may be a new target for antigen-specific immunotherapy against EML4-ALK-positive cancers.

A peptide antigen derived from EGFR T790M is immunogenic in non-small cell lung cancer

“…To evaluate the immunogenic potential of the five predicted HLA-A * 02:01-binding peptides derived from EGFR T790M, we attempted to induce peptide-specific CTLs from human PBMCs obtained from four healthy donors. Several reports have shown the usefulness of artificial antigen-presenting cells (aAPCs) for the induction and expansion of peptide-specific CTLs from PBMCs ( 23 , 24 ). Thus, we attempted to induce such CTLs using aAPCs.…”

Composite biomarkers defined by multiparametric immunofluorescence analysis identify ALK-positive adenocarcinoma as a potential target for immunotherapy

“…Previous studies have reported that peptides derived from chimeric ALK protein could generate anti-ALK-specific CD8 C T cells. 36 These cells have also been detected in cancer patients with ALK rearrangements. 26,27 We did not investigate the presence of anti-ALK-specific T cells in our series of ALK-positive ADC, but indirect arguments suggest that antitumor CD8 C T cells were present.…”

HLABAP: HLA Class I-Binding Antigenic Peptide Predictor

“…A substantial number of HLA-A*02:01-restricted cytotoxic T lymphocyte epitopes closely related to tumors have been identified so far [8]. In order to illustrate the performance of HLABAP, the experimentally determined pIC50 values and the predicted binding affinities of the peptides against HLA-A*02:01 were compared in this study.…”