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

The influence of families on early adolescent school connectedness: Evidence that this association varies with adolescent involvement in peer drinking networks

School connectedness is central to the long term well-being of adolescents, and high quality parent-child relationships facilitate school connectedness. This study examined the extent to which family relationship quality is associated with the school connectedness of pre- and early teenagers, and how this association varies with adolescent involvement in peer drinking networks. The sample consisted of 7,372 10-14 year olds recruited from 231 schools in 30 Australian communities. Participants completed the Communities that Care youth survey. A multi-level model of school connectedness was used, with a random term for school-level variation. Key independent variables included family relationship quality, peer drinking networks, and school grade. Control variables included child gender, sensation seeking, depression, child alcohol use, parent education, and language spoken at home. For grade 6 students, the association of family relationship quality and school connectedness was lower when peer drinking networks were present, and this effect was nonsignificant for older (grade 8) students. Post hoc analyses indicated that the effect for family relationship quality on school connectedness was nonsignificant when adolescents in grade 6 reported that the majority of friends consumed alcohol. The results point to the importance of familyschool partnerships in early intervention and prevention