PMID- 35798537
OWN - NLM
STAT- MEDLINE
DCOM- 20220711
LR  - 20220813
IS  - 2051-1426 (Electronic)
IS  - 2051-1426 (Linking)
VI  - 10
IP  - 7
DP  - 2022 Jul
TI  - Natural high-avidity T-cell receptor efficiently mediates regression of 
      cancer/testis antigen 83 positive common solid cancers.
LID - 10.1136/jitc-2022-004713 [doi]
LID - e004713
AB  - BACKGROUND: T-cell receptor-engineered T cells (TCR-Ts) have achieved encouraging 
      success in anticancer clinical trials. The antigenic targets, however, were 
      primarily focused on human leukocyte antigen (HLA) A*02:01 restricted epitopes 
      from a few cancer/testis antigens (CTAs) which are not widely expressed in common 
      solid cancers; the tested T-cell receptors (TCRs) were frequently from 
      tumor-infiltrating lymphocytes of old patients and were not assured to have 
      higher avidity. Here, we propose the isolation of high-avidity TCRs against CTAs 
      that are frequently expressed in common solid cancers. METHODS: We selected the 
      CT83 protein, which is frequently expressed in common solid cancers, as a model 
      antigen for screening of its specific TCR. The predicted CT83 epitopes with 
      strong or weak binding to HLA-I molecules, popular in the Chinese population, 
      were integrated into three synthetic long peptides. CT83 reactive CD8+ T cells 
      were stimulated with peptide-loaded dendritic cells (DCs) and sorted using the 
      CD137 biomarker for single-cell sequencing to obtain the paired TCRalphabeta sequence. 
      The higher frequency TCRs were reconstructed for characterization of the CT83 
      epitope and for assessment of in vitro and in vivo antitumor activities. RESULTS: 
      CT83 reactive T cells from young healthy donors (YHDs) were generated by repeated 
      stimulation with DCs and peptides. The single-cell TCR sequencing results of 
      reactive T cells indicated that a single TCR clonotype dominated the paired TCRs. 
      T cells engineered with this dominant TCR led to HLA-A*11:01-restricted 
      recognition of the CT83(14-22) epitope, with higher avidity. Functional assays 
      showed powerful cytotoxicity in vitro against the targets of several 
      CT83-positive solid cancer cell lines. Furthermore, TCR-Ts showed therapeutic 
      efficacy in three xenograft solid tumor models. The meta-analysis of gene 
      expression of 92 CTAs indicated that most CTAs did not or at low levels in the 
      thymus, which suggested that those CTAs may experience incomplete thymic central 
      tolerance. CONCLUSIONS: High-avidity TCR against CT83 could be isolated from YHDs 
      and efficiently mediate regression of well-established xenograft common solid 
      tumors. The high-avidity TCR repertoire in the peripheral blood of some donors 
      for CT83 and other CTAs provides the basis for the efficient isolation of 
      high-avidity TCRs to target numerous solid cancers.
CI  - (c) Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published 
      by BMJ.
FAU - Li, Qingyang
AU  - Li Q
AUID- ORCID: 0000-0003-0811-5067
AD  - Department of Clinical Oncology, the First Affiliated Hospital of Jinan 
      University, Guangzhou, China.
FAU - Hu, Wei
AU  - Hu W
AUID- ORCID: 0000-0003-4288-2307
AD  - T Cell Immune Technology Co., Ltd, Guangzhou, China.
FAU - Liao, Baoyi
AU  - Liao B
AUID- ORCID: 0000-0003-3455-0214
AD  - Department of Clinical Oncology, the First Affiliated Hospital of Jinan 
      University, Guangzhou, China.
FAU - Song, Chanchan
AU  - Song C
AUID- ORCID: 0000-0002-3665-0297
AD  - Department of Clinical Oncology, the First Affiliated Hospital of Jinan 
      University, Guangzhou, China.
FAU - Li, Liangping
AU  - Li L
AUID- ORCID: 0000-0001-5832-548X
AD  - Department of Clinical Oncology, the First Affiliated Hospital of Jinan 
      University, Guangzhou, China liangping_li@jnu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Immunother Cancer
JT  - Journal for immunotherapy of cancer
JID - 101620585
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (CT83 protein, human)
RN  - 0 (Epitopes)
RN  - 0 (HLA-A Antigens)
RN  - 0 (Peptides)
RN  - 0 (Receptors, Antigen, T-Cell)
SB  - IM
MH  - *Antigens, Neoplasm
MH  - Epitopes
MH  - HLA-A Antigens
MH  - Humans
MH  - *Neoplasms
MH  - Peptides
MH  - *Receptors, Antigen, T-Cell
PMC - PMC9263944
OTO - NOTNLM
OT  - T-lymphocytes
OT  - antigens, neoplasm
OT  - epitope mapping
OT  - immunotherapy, adoptive
OT  - receptors, antigen
COIS- Competing interests: LL and QL were inventors on a filed China patent application 
      for the CT83/TCR1 described in the study (202111390174.X)
EDAT- 2022/07/08 06:00
MHDA- 2022/07/12 06:00
PMCR- 2022/07/07
CRDT- 2022/07/07 21:13
PHST- 2022/06/13 00:00 [accepted]
PHST- 2022/07/07 21:13 [entrez]
PHST- 2022/07/08 06:00 [pubmed]
PHST- 2022/07/12 06:00 [medline]
PHST- 2022/07/07 00:00 [pmc-release]
AID - jitc-2022-004713 [pii]
AID - 10.1136/jitc-2022-004713 [doi]
PST - ppublish
SO  - J Immunother Cancer. 2022 Jul;10(7):e004713. doi: 10.1136/jitc-2022-004713.