Abstract
Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, has achieved high clinical response rates in patients with non–small cell lung cancers (NSCLCs). However, over time, most tumors develop acquired resistance to EGFR-TKIs, which is associated with the secondary EGFR T790M resistance mutation in about half the cases. Currently there are no effective treatment options for patients with this resistance mutation. Here we identified two novel HLA-A*0201 (A2)-restricted T cell epitopes containing the mutated methionine residue of the EGFR T790M mutation, T790M-5 (MQLMPFGCLL) and T790M-7 (LIMQLMPFGCL), as potential targets for EGFR-TKI-resistant patients. When peripheral blood cells were repeatedly stimulated in vitro with these two peptides and assessed by antigen-specific IFN-γ secretion, T cell lines responsive to T790M-5 and T790M-7 were established in 5 of 6 (83%) and 3 of 6 (50%) healthy donors, respectively. Additionally, the T790M-5- and T790M-7-specific T cell lines displayed an MHC class I-restricted reactivity against NSCLC cell lines expressing both HLA-A2 and the T790M mutation. Interestingly, the NSCLC patients with antigen-specific T cell responses to these epitopes showed a significantly less frequency of EGFR-T790M mutation than those without them [1 of 7 (14%) vs 9 of 15 (60%); chi-squared test, p = 0.0449], indicating the negative correlation between the immune responses to the EGFR-T790M-derived epitopes and the presence of EGFR-T790M mutation in NSCLC patients. This finding could possibly be explained by the hypothesis that immune responses to the mutated neo-antigens derived from T790M might prevent the emergence of tumor cell variants with the T790M resistance mutation in NSCLC patients during EGFR-TKI treatment. Together, our results suggest that the identified T cell epitopes might provide a novel immunotherapeutic approach for prevention and/or treatment of EGFR-TKI resistance with the secondary EGFR T790M resistance mutation in NSCLC patients.
Highlights
Lung cancer is one of the most aggressive malignancies, but recently significant progress has been made in the therapeutic strategy against this disease [1,2,3,4]
The WT-5 peptide containing the wild-type threonine residue at position 790 of epidermal growth factor receptor (EGFR), which corresponded to T790M-5, showed high binding capability to HLA-A2, whereas the WT-7 peptide corresponding to T790M-7 did not bind to HLA-A2
The clinical benefit of EGFR-TKIs has been demonstrated in non–small cell lung cancers (NSCLCs) patients with activating EGFR mutations [8,9,10], but most tumors develop acquired resistance via several different mechanisms, including the secondary T790M mutation that occurs in around 50% of patients with EGFR-TKI resistance [11,12,13,14,15]
Summary
Lung cancer is one of the most aggressive malignancies, but recently significant progress has been made in the therapeutic strategy against this disease [1,2,3,4]. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, have been developed as a novel treatment option for patients with non–small cell lung cancers (NSCLCs) that possess somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene [5,6,7]. Prospective clinical trials of EGFR-TKI treatment in NSCLC patients with activating EGFR mutations, such as delE746-A750 (exon 19) and L858R (exon 21), have demonstrated high clinical response rates of approximately 80% [8,9,10]. There have been no effective treatment options for NSCLC patients with this secondary T790M resistance mutation
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