EGFR T790M mutation as a possible target for immunotherapy; identification of HLA-A*0201-restricted T cell epitopes derived from the EGFR T790M mutation.
EGFR T790M mutation as a possible target for immunotherapy; identification of HLA-A*0201-restricted T cell epitopes derived from the EGFR T790M mutation.
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DOI：
10.1371/journal.pone.0078389
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sasada T
中科院分区：
文献类型：
--
作者：
Yamada T;Azuma K;Muta E;Kim J;Sugawara S;Zhang GL;Matsueda S;Kasama-Kawaguchi Y;Yamashita Y;Yamashita T;Nishio K;Itoh K;Hoshino T;Sasada T
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs），如吉非替尼和厄洛替尼，在非小细胞肺癌（nsclc）患者中获得了很高的临床缓解率。然而，随着时间的推移，大多数肿瘤对EGFR- tkis产生获得性耐药，在大约一半的病例中，这与继发性EGFR T790M耐药突变有关。目前对于这种耐药突变的患者没有有效的治疗选择。在这里，我们发现了两个新的HLA-A*0201 （A2）限制性T细胞表位，包含EGFR T790M突变的突变蛋氨酸残基，T790M-5 （MQLMPFGCLL）和T790M-7 (LIMQLMPFGCL)，作为EGFR- tki耐药患者的潜在靶点。用这两种多肽在体外反复刺激外周血细胞，并通过抗原特异性IFN-γ分泌进行评估，6名健康供者中有5名（83%）和3名（50%）分别建立了对T790M-5和T790M-7有反应的T细胞系。此外，T790M-5和T790M-7特异性T细胞系对同时表达HLA-A2和T790M突变的NSCLC细胞系表现出MHC i类限制性反应性。有趣的是，对这些表位有抗原特异性T细胞反应的NSCLC患者的EGFR-T790M突变频率明显低于没有这些表位的患者[1 / 7 (14%)vs 9 / 15 (60%)；卡方检验，p = 0.0449]，提示NSCLC患者对EGFR-T790M源性表位的免疫应答与EGFR-T790M突变存在负相关。这一发现可能可以通过以下假设来解释：在EGFR-TKI治疗期间，NSCLC患者对源自T790M的突变新抗原的免疫应答可能阻止了T790M耐药突变肿瘤细胞变体的出现。总之，我们的研究结果表明，鉴定的T细胞表位可能为预防和/或治疗NSCLC患者继发性EGFR T790M耐药突变的EGFR- tki耐药提供了一种新的免疫治疗方法。
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.
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