Identification of NY-ESO-1157-165 Specific Murine T Cell Receptors With Distinct Recognition Pattern for Tumor Immunotherapy.

Helin Zhang,Bin Zeng,Meng Sun,Jie Wang,Shuguang Tan,George F Gao,Yi Han,Xiaoqing Cao

doi:10.3389/fimmu.2021.644520

Abstract

New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is a promising target for T-cell receptor-engineered T cell (TCR-T) therapy, and targeting the human leukocyte antigen (HLA)-A2 restricted NY-ESO-1157−165 epitope has yielded remarkable clinical benefits in the treatment of multiple advanced malignancies. Herein, we report the identification of two NY-ESO-1157−165 epitope-specific murine TCRs obtained from HLA-A*0201 transgenic mice. NY-ESO-1157−165 specific TCRs were isolated after vaccinating HLA-A2 transgenic mice with epitope peptides. HZ6 and HZ8 TCRs could specifically bind to NY-ESO-1157−165/HLA-A2 and were capable of cytokine secretion with engineered Jurkat T cells and primary T cells upon recognition with K562 target cells expressing the single-chain trimer (SCT) of NY-ESO-1157−165/HLA-A2. The reactivity profiles of the HZ6 and HZ8 TCRs were found to be distinct from one another when co-cultured with K562 target cells carrying alanine-substituted NY-ESO-1157−165 SCTs. The binding characterization revealed that the recognition pattern of the HZ6 TCR to NY-ESO-1157−165/HLA-A2 was substantially different from the widely used 1G4 TCR. These findings would broaden the understanding of immunogenicity of the NY-ESO-1157−165, and the two identified TCRs may serve as promising candidates for the future development of TCR-T therapy for tumors.

Highlights

Engineered T cell-based immunotherapy, mainly referred to as chimeric antigen receptor engineered T cell (CAR-T) and T-cell receptor engineered T-cell (TCR-T) therapy, has emerged as novel therapeutic strategies for a variety of tumors [1, 2]
Antigen-specific T cells were single-cell isolated from splenocytes with NY-ESO-1157−165/human leukocyte antigen (HLA)-A2 tetramer using flow cytometry
NY-ESO-1157−165/HLA-A2 tetramer staining positive CD8+ T cells were identified in two mice from two independent experiments, with a total of six peptide-immunized mice: Mus2 from the first batch and Mus-177 from the second batch (Figures 1B,C)

Summary

Introduction

Engineered T cell-based immunotherapy, mainly referred to as chimeric antigen receptor engineered T cell (CAR-T) and T-cell receptor engineered T-cell (TCR-T) therapy, has emerged as novel therapeutic strategies for a variety of tumors [1, 2]. New York esophageal squamous cell carcinoma 1 antigen (NY-ESO-1), a member of the cancer-testis antigen family, is considered a promising target for TCR-T cell immunotherapy. It is frequently overexpressed in various types of tumors, and its expression in normal tissue is restricted to germ cells, which can be exploited to avoid on-target toxicity as a therapeutic target [8,9,10]. Among these TCRs, 1G4, which has been extensively investigated, with clear recognition mechanisms with NY-ESO-1157−165 [17, 18], is currently undergoing multiple clinical trials for a range of advanced solid tumors [11], and striking clinical responses have been observed in patients with advanced multiple myeloma and synovial cell sarcoma [19,20,21,22,23]

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