Endogenous CD4+ T Cells Recognize Neoantigens in Lung Cancer Patients, Including Recurrent OncogenicKRASandERBB2(Her2) Driver Mutations

Abstract

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. Much of the focus has been on identifying epitopes presented to CD8 þ T cells by class I MHC. However, CD4 þ class II MHC-restricted T cells have been shown to have an important role in antitumor immunity. Unfortunately, the vast majority of neoantigens recognized by CD8 þ or CD4 þ T cells in cancer patients result from random mutations and are patient-specific. Here, we screened the blood of 5 non-small cell lung cancer (NSCLC) patients for T-cell responses to candidate mutation-encoded neoepitopes. T-cell responses were detected to 8.8% of screened antigens, with 1 to 7 antigens identified per patient. A majority of responses were to random, patient-specific mutations.However, CD4 þ 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. 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. Deep sequencing identified the Her2-ITDspecific TCR in the tumor but not nonadjacent lung. Our results showed that CD4 þ T-cell responses to neoantigens, including recurrent driver mutations, can be derived from the blood of NSCLC patients. These data support the use of adoptive transfer or vaccination to augment CD4 þ neoantigen-specific T cells and elucidate their role in human antitumor immunity.

Harnessing neoantigen specific CD4 T cells for cancer immunotherapy

“…Although additional bioinformatics packages exist that may be used to augment the performance of MHC prediction algorithms, a recent study from our colleagues in the Peters lab found that the addition of predictions for proteasomal cleavage, TAP transport, and MHC‐peptide complex stability did not improve the predictive power of NetMHCpan—a widely used prediction algorithm for MHC I binding 46 . Lastly, in a study from the Riddell group, mutations were selected for screening in an HLA agnostic manner 47 . Instead, mutations were ranked based on their mean expression levels in The Cancer Genome Atlas for the given cancer type or expression as determined by RNA sequencing of a patient‐derived xenograft.…”

The role and therapeutic implications of T cells in cancer of the lung

“…Despite this, emerging evidence has suggested that in lung cancer, these CD4 + T cells are prognostically significant, with increased tumor-infiltrating CD4 + T cells correlated to improved survival. 23 19 Furthermore, recent research has demonstrated CD4 + T cells to be important in instigating recognition of neoantigens and driver mutations in human NSCLC tumors, with endogenous responses demonstrated in patients.…”

Neoantigen-specific CD4+T-cell response is critical for the therapeutic efficacy of cryo-thermal therapy

“… 20 23–25 Endogenous CD4 + T-cells recognizing neoantigens have been found in patients with cancer. 26 27 Neoantigen-specific CD4 + T-cell responses can mediate the regression of metastatic epithelial cancer. 28 CD4 + T-cell neoepitopes-based vaccination in tumor-bearing mice resulted in rejection of established B16F10 melanoma and CT26 colon tumor models.…”