TCR-engineered T cells targeting a shared β-catenin mutation eradicate solid tumors.

HLA-bound peptides encoded by recurrent driver mutations are candidate targets for T cell-directed immunotherapy. Here we identify two neopeptides encoded by the CTNNB1 mutation presented on the frequent HLA-A*02:01 and HLA-A*24:02 molecules in cell lines naturally expressing the mutation and HLA alleles. This mutation leads to a gain of function in β-catenin and is estimated to occur in >7,000 new cancer cases annually in the United States.

Translation dysregulation in cancer as a source for targetable antigens.

Aberrant peptides presented by major histocompatibility complex (MHC) molecules are targets for tumor eradication, as these peptides can be recognized as foreign by T cells. Protein synthesis in malignant cells is dysregulated, which may result in the generation and presentation of aberrant peptides that can be exploited for T cell-based therapies. To investigate the role of translational dysregulation in immunological tumor control, we disrupt translation fidelity by deleting tRNA wybutosine (yW)-synthesizing protein 2 (TYW2) in tumor cells and characterize the downstream impact on translation fidelity and immunogenicity using immunopeptidomics, genomics, and functional assays.

Pre-depletion of TRBC1+ T cells promotes the therapeutic efficacy of anti-TRBC1 CAR-T for T-cell malignancies.

Targeting T cell receptor β-chain constant region 1 (TRBC1) CAR-T could specifically kill TRBC1+ T-cell malignancies. However, over-expressed CARs on anti-TRBC1 CAR transduced TRBC1+ T cells (CAR-C1) bound to autologous TRBC1, masking TRBC1 from identification by other anti-TRBC1 CAR-T, and moreover only the remaining unoccupied CARs recognized TRBC1+ cells, considerably reducing therapeutic potency of CAR-C1. In addition, co-culture of anti-TRBC1 CAR-T and TRBC1+ cells could promote exhaustion and terminal differentiation of CAR-T.

Isolation of T cell receptor specifically reactive with autologous tumour cells from tumour-infiltrating lymphocytes and construction of T cell receptor engineered T cells for esophageal squamous cell carcinoma.

Background: T cell receptor-engineered T cells (TCR-Ts) therapy is a promising cancer treatment strategy. Nowadays, most studies focused on identification of high-avidity T cell receptors (TCRs) directed against neoantigens derived from somatic mutations. However, few neoantigens per patient could induce immune response in epithelial cancer and additionally many tumor-specific antigens could be derived from noncoding region.

Immediate and substantial evolution of T-cell repertoire in peripheral blood and tumor microenvironment of patients with esophageal squamous cell carcinoma treated with preoperative chemotherapy.

Preoperative chemotherapy could decrease tumor size and improve overall survival for esophageal squamous cell carcinoma (ESCC), and moreover, rational combination of chemotherapy and immunotherapy could increase likelihood of inducing an effective antitumor immune response. However, the immunologic impact of chemotherapeutic drugs originally chosen for cancer treatment due to the direct toxicity is poorly understood. We assess the effect of a combination of clinically approved chemotherapeutic drugs [paclitaxel-nedaplatin (PTX-NDP)] on T-cell receptor (TCR) repertoires of peripheral T cells and tumor-infiltrating lymphocytes (TILs) from five patients with primary ESCC.

TCR repertoire intratumor heterogeneity of CD4 and CD8 T cells in centers and margins of localized lung adenocarcinomas.

Intratumor heterogeneity (ITH) of T cell receptor (TCR) repertoire in different T-cell subsets and locations in lung adenocarcinomas was unclear. Here, we investigated percentages and TCR repertoire of freshly isolated CD4 and CD8 tumor infiltrating lymphocytes (TILs) in tumor centers and margins by flow cytometry on 80 tumor samples from 20 patients and high-throughput TCR sequencing on 27 and 25 samples of CD4 and CD8 TILs from seven patients. Our results demonstrated that amount and TCR repertoire diversity of CD4 TILs were significantly higher than those of CD8 TILs and moreover substantial ITH regarding amount and TCR repertoire of CD4 and CD8 TILs were observed.

Mutation analysis of the EBV-lymphoblastoid cell line cautions their use as antigen-presenting cells.

Lymphoblastoid cell lines (LCLs) have been widely used as professional antigen-presenting cells (APCs). However, neoantigen-loaded LCLs could induce nonspecific T-cell response, which could be due to expression of both Epstein-Barr virus (EBV) antigens and nonsynonymous mutations arising in LCLs. Since the number of passages could influence mutational characteristics of LCLs, and moreover extensive proliferation of LCLs in vitro is necessary to activate T cells for immunotherapy, we comprehensively profiled mutational characteristics by comparing eight sets of B cells and matched high-passage LCLs using whole-exome sequencing in order to assess the effect of nonsynonymous mutations arising in LCLs on nonspecific T-cell response.