T cells specific for neoantigens encoded by mutated genes have been implicated as important mediators of antitumor immunity in patients receiving checkpoint blocking antibodies ( 1) and adoptive T-cell transfer ( 2, 3). T cells can eliminate cancer cells through recognition of peptides derived from the processing of nonmutated or mutated proteins and presented bound to cell-surface MHC molecules. These data support the use of adoptive transfer or vaccination to augment CD4 + neoantigen-specific T cells and elucidate their role in human antitumor immunity. Our results showed that CD4 + T-cell responses to neoantigens, including recurrent driver mutations, can be derived from the blood of NSCLC patients. Deep sequencing identified the Her2-ITD–specific TCR in the tumor but not nonadjacent lung. Two different T-cell receptors (TCR) specific for KRAS G12V and one T-cell receptor specific for Her2-ITD were isolated and conferred antigen specificity when transfected into T cells. However, CD4 + T cells that recognized the recurrent KRAS G12V and the ERBB2 ( Her2) internal tandem duplication (ITD) oncogenic driver mutations, but not the corresponding wild-type sequences, were identified in two patients. A majority of responses were to random, patient-specific mutations. T-cell responses were detected to 8.8% of screened antigens, with 1 to 7 antigens identified per patient. Here, we screened the blood of 5 non–small cell lung cancer (NSCLC) patients for T-cell responses to candidate mutation-encoded neoepitopes. Unfortunately, the vast majority of neoantigens recognized by CD8 + or CD4 + T cells in cancer patients result from random mutations and are patient-specific. However, CD4 + class II MHC-restricted T cells have been shown to have an important role in antitumor immunity. Much of the focus has been on identifying epitopes presented to CD8 + T cells by class I MHC. T cells specific for neoantigens encoded by mutated genes in cancers are increasingly recognized as mediators of tumor destruction after immune-checkpoint inhibitor therapy or adoptive cell transfer.
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