Identification of neoantigen-specific T cells and their targets: implications for immunotherapy of head and neck squamous cell carcinoma

Oncoimmunology. 2019 Feb 6;8(4):e1568813. doi: 10.1080/2162402X.2019.1568813. eCollection 2019.

Abstract

To develop a practically applicable method for T-cell receptor (TCR)-engineered T cell immunotherapy targeting neoantigens, we have been attempting to identify neoantigen-specific T cell receptors (TCRs) and establish TCR-engineered T cells in a 3-4-month period. In this study, we report the characterization of T cell repertoires in tumor microenvironment (TME) and identification of neoantigen-specific TCRs after stimulation of patient-derived T cells. We screened 15 potential neoantigen peptides and successfully identified two CD8+HLA-dextramer+ T cells, which recognized MAGOHBG17A and ZCCHC14P368L. All three dominant TCR clonotypes from MAGOHBG17A-HLA dextramer-sorted CD8+ T cells were also found in T cells in TME, while none of dominant TCR clonotypes from ZCCHC14P368L-HLA dextramer-sorted CD8+ T cells was found in the corresponding TME. The most dominant TCRA/TCRB pairs for these two neoantigens were cloned into HLA-matched healthy donors' T lymphocytes to generate TCR-engineered T cells. The functional assay showed MAGOHBG17A TCR-engineered T cells could be significantly activated in a mutation-specific, HLA-restricted and peptide-dose-dependent manner while ZCCHC14P368L TCR-engineered T cells could not. Our data showed neoantigen-reactive T cell clonotypes that were identified in the patient's peripheral blood could be present in the corresponding TME and might be good TCRs targeting neoantigens.

Keywords: Head and neck squamous cell carcinoma (HNSCC); T cell receptor (TCR); adoptive T cell therapy; cytotoxic T lymphocyte (CTL); engineered T cells; neoantigen.

Publication types

  • Research Support, Non-U.S. Gov't

Grant support

This work was supported partly by a research grant from OncoTherapy Science, Inc.