EGFR T790M mutation as a possible target for immunotherapy; identification of HLA-A*0201-restricted T cell epitopes derived from the EGFR T790M mutation.
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.
Department of Immunology and Immunotherapy, Kurume University School of Medicine, Kurume, Fukuoka, Japan ; Department of Surgery, Fukuoka University School of Medicine, Fukuoka, Fukuoka, Japan.
Teppei
T
Yamada
Koichi
K
Azuma
Emi
E
Muta
Jintaek
J
Kim
Shunichi
S
Sugawara
Guang Lan
GL
Zhang
Satoko
S
Matsueda
Yuri
Y
Kasama-Kawaguchi
Yuichi
Y
Yamashita
Takuto
T
Yamashita
Kazuto
K
Nishio
Kyogo
K
Itoh
Tomoaki
T
Hoshino
Tetsuro
T
Sasada
D000368:Aged; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D015789:HLA-A2 Antigen / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000276:immunology / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use
D000970:Antineoplastic Agents; D018984:Epitopes, T-Lymphocyte; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010455:Peptides; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib