PMID- 35959968
OWN - NLM
STAT- MEDLINE
DCOM- 20220815
LR  - 20220825
IS  - 2095-3941 (Print)
IS  - 2095-3941 (Linking)
VI  - 18
IP  - 4
DP  - 2021 Nov 24
TI  - Residue substitution enhances the immunogenicity of neoepitopes from gastric 
      cancers.
PG  - 1053-65
LID - j.issn.2095-3941.2021.0022 [pii]
LID - 10.20892/j.issn.2095-3941.2021.0022 [doi]
AB  - OBJECTIVE: Neoantigens arising from gene mutations in tumors can induce specific 
      immune responses, and neoantigen-based immunotherapies have been tested in 
      clinical trials. Here, we characterized the efficacy of altered neoepitopes in 
      improving immunogenicity against gastric cancer. METHODS: Raw data of whole-exome 
      sequencing derived from a patient with gastric cancer were analyzed using 
      bioinformatics methods to identify neoepitopes. Neoepitopes were modified by P1Y 
      (the first amino acid was replaced by tyrosine) and P2L (the second amino acid 
      was replaced by leucine). T2 binding and stability assays were used to detect the 
      affinities between the neoepitopes and the HLA molecules, as well as the 
      stabilities of complexes. Dendritic cells (DCs) presented with neoepitopes 
      stimulated naive CD8(+) T cells to induce specific cytotoxic T lymphocytes. ELISA 
      and carboxyfluorescein succinimidyl ester were used to detect IFN-gamma and TNF-alpha 
      levels, and T cell proliferation. Perforin was detected by flow cytometry. The 
      cytotoxicity of T cells was determined using the lactate dehydrogenase assay. 
      RESULTS: Bioinformatics analysis, T2 binding, and stability assays indicated that 
      residue substitution increased the affinity between neoepitopes and HLA 
      molecules, as well as the stabilities of complexes. DCs presented with altered 
      neoepitopes stimulated CD8(+)T cells to release more IFN-gamma and had a greater 
      effect on promoting proliferation than wild-type neoepitopes. CD8(+)T cells 
      stimulated with altered neoepitopes killed more wild-type neoepitope-pulsed T2 
      cells than those stimulated with wild-type neoepitopes, by secreting more IFN-gamma, 
      TNF-alpha, and perforin. CONCLUSIONS: Altered neoepitopes exhibited greater 
      immunogenicity than wild-type neoepitopes. Residue substitution could be used as 
      a new strategy for immunotherapy to target neoantigens.
CI  - Copyright (c) 2021 Cancer Biology & Medicine.
FAU - Yu, Huahui
AU  - Yu H
AD  - The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, 
      China.
FAU - Li, Jieyu
AU  - Li J
AD  - Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University 
      Cancer Hospital, Fuzhou 350014, China.
AD  - Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, China.
FAU - Yuan, Yuan
AU  - Yuan Y
AD  - BGI-Shenzhen, Shenzhen 518083, China.
AD  - BGI Education Center, University of Chinese Academy of Sciences, Shenzhen 518083, 
      China.
FAU - Chen, Yu
AU  - Chen Y
AD  - Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, China.
AD  - Department of Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer 
      Hospital, Fuzhou 350014, China.
FAU - Hong, Jingwen
AU  - Hong J
AD  - The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, 
      China.
FAU - Ye, Chunmei
AU  - Ye C
AD  - The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, 
      China.
FAU - Lin, Wansong
AU  - Lin W
AD  - Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University 
      Cancer Hospital, Fuzhou 350014, China.
AD  - Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, China.
FAU - Chen, Huijing
AU  - Chen H
AD  - Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University 
      Cancer Hospital, Fuzhou 350014, China.
AD  - Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, China.
FAU - Guo, Zengqing
AU  - Guo Z
AD  - Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, China.
AD  - Department of Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer 
      Hospital, Fuzhou 350014, China.
FAU - Li, Bo
AU  - Li B
AD  - BGI-Shenzhen, Shenzhen 518083, China.
FAU - Ye, Yunbin
AU  - Ye Y
AUID- ORCID: 0000-0002-0256-987X
AD  - The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, 
      China.
AD  - Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University 
      Cancer Hospital, Fuzhou 350014, China.
AD  - Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - China
TA  - Cancer Biol Med
JT  - Cancer biology & medicine
JID - 101588850
RN  - 0 (Amino Acids)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 126465-35-8 (Perforin)
SB  - IM
MH  - Amino Acids/metabolism
MH  - *CD8-Positive T-Lymphocytes
MH  - Humans
MH  - Perforin/metabolism
MH  - *Stomach Neoplasms/genetics/metabolism/therapy
MH  - Tumor Necrosis Factor-alpha/metabolism
PMC - PMC8610152
OTO - NOTNLM
OT  - Gastric cancer
OT  - bioinformatics
OT  - immunotherapy
OT  - neoepitope
OT  - residue substitution
COIS- No potential conflicts of interest are disclosed.
EDAT- 2022/08/13 06:00
MHDA- 2022/08/16 06:00
PMCR- 2021/11/15
CRDT- 2022/08/12 08:43
PHST- 2022/08/12 08:43 [entrez]
PHST- 2022/08/13 06:00 [pubmed]
PHST- 2022/08/16 06:00 [medline]
PHST- 2021/11/15 00:00 [pmc-release]
AID - j.issn.2095-3941.2021.0022 [pii]
AID - 10.20892/j.issn.2095-3941.2021.0022 [doi]
PST - ppublish
SO  - Cancer Biol Med. 2021 Nov 24;18(4):1053-65. doi: 
      10.20892/j.issn.2095-3941.2021.0022.