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

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 MAGOHB G17A and ZCCHC14 P368L . All three dominant TCR clonotypes from MAGOHB G17A -HLA dextramer-sorted CD8 + T cells were also found in T cells in TME, while none of dominant TCR clonotypes from ZCCHC14 P368L -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 MAGOHB G17A TCR-engineered T cells could be significantly activated in a mutation-specific, HLA-restricted and peptide-dose-dependent manner while ZCCHC14 P368L 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.

Recurrent Neoantigens in Colorectal Cancer as Potential Immunotherapy Targets

“…However, not all CRC patients with MSI-H show clinical efficacy in ICI treatment. Neoantigen-based immunotherapy is complementary to ICIs since it has no specific requirement for patient's MSI status nor tumor mutation burden (TMB) [6,7]. Previous studies on CRC genomics mainly focused on the mech-anism of tumor development and metastasis and less involves neoantigen and neoantigen-based immunotherapy [8][9][10][11][12][13].…”

Point mutation screening of tumor neoantigens and peptide‑induced specific cytotoxic T lymphocytes using The Cancer Genome Atlas database

“…The cytotoxiceffect of CTLs induced by mutant peptides in the three groups was similar in both wild-type and mutant tumor cells, which may be associated with the cross-recognition effect of T cells. As there was only one amino acid difference between the mutant and wild-type peptides, there were two types of antigenic peptide-MHC complexes that were recognized by specific, effective CD8 + T cells (22). The present results indicate that specific CTLs, induced by mutant peptides, can kill both mutant and wild-type tumor cells.…”

Parameters for Optoperforation-Induced Killing of Cancer Cells Using Gold Nanoparticles Functionalized With the C-terminal Fragment of Clostridium Perfringens Enterotoxin

“…Some reports show that manipulating the tumor environment could induce immune cells to attack the tumor [19,21,22,23]. Other reports show that tumor cells express neoantigens, but these antigens are not present on the surface of the tumor cells due to loss of HLA class I by tumor cells [24,25,26]. By inducing the necrosis, it may be possible to liberate these tumor antigens in the tumor interstitial spaces.…”

“…Such tumor neoantigens are expressed by tumor cells. However, they are maintained in the cells and rarely presented to the immune cells due to loss of HLA class I by tumor cells [24,25,26]. By inducing necrosis in tumor, it may be possible to increase the presence of these tumor antigens in the extracellular space within the tumor.…”