PMID- 35665491
OWN - NLM
STAT- MEDLINE
DCOM- 20220808
LR  - 20220809
IS  - 2198-3844 (Electronic)
IS  - 2198-3844 (Linking)
VI  - 9
IP  - 22
DP  - 2022 Aug
TI  - Hepatobiliary Tumor Organoids Reveal HLA Class I Neoantigen Landscape and 
      Antitumoral Activity of Neoantigen Peptide Enhanced with Immune Checkpoint 
      Inhibitors.
PG  - e2105810
LID - 10.1002/advs.202105810 [doi]
LID - 2105810
AB  - Neoantigen-directed therapy lacks preclinical models recapitulating neoantigen 
      characteristics of original tumors. It is urgent to develop a platform to assess 
      T cell response for neoantigen screening. Here, immunogenic potential of 
      neoantigen-peptides of tumor tissues and matched organoids (n = 27 pairs) are 
      analyzed by Score tools with whole genome sequencing (WGS)-based human leukocyte 
      antigen (HLA)-class-I algorithms. The comparisons between 9203 predicted 
      neoantigen-peptides from 2449 mutations of tumor tissues and 9991 ones from 2637 
      mutations of matched organoids demonstrate that organoids preserved majority of 
      genetic features, HLA alleles, and similar neoantigen landscape of original 
      tumors. Higher neoantigen load is observed in tumors with early stage. Multiomics 
      analysis combining WGS, RNA-seq, single-cell RNA-seq, mass spectrometry filters 
      out 93 candidate neoantigen-peptides with strong immunogenic potential for 
      functional validation in five organoids. Immunogenic peptides are defined by 
      inducing increased CD107aCD137IFN-gamma expressions and IFN-gamma secretion of CD8 cells 
      in flow cytometry and enzyme-linked immunosorbent assay assays. Nine immunogenic 
      peptides shared by at least two individuals are validated, including peptide from 
      TP53(R90S) . Organoid killing assay confirms the antitumor activity of validated 
      immunogenic peptide-reactive CD8 cells, which is further enhanced in the presence 
      of immune checkpoint inhibitors. The study characterizes HLA-class-I neoantigen 
      landscape in hepatobiliary tumor, providing practical strategy with tumor 
      organoid model for neoantigen-peptide identification in personalized 
      immunotherapy.
CI  - (c) 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.
FAU - Wang, Wenwen
AU  - Wang W
AD  - Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical 
      College, Fudan University, Shanghai, 200032, China.
FAU - Yuan, Tinggan
AU  - Yuan T
AD  - School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, 
      China.
AD  - CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and 
      Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, 200031, China.
AD  - University of Chinese Academy of Sciences, Beijing, 100049, China.
FAU - Ma, Lili
AU  - Ma L
AD  - School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, 
      China.
AD  - CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and 
      Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, 200031, China.
AD  - University of Chinese Academy of Sciences, Beijing, 100049, China.
FAU - Zhu, Yanjing
AU  - Zhu Y
AD  - The International Cooperation Laboratory on Signal Transduction, Eastern 
      Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 
      200438, China.
AD  - National Center for Liver Cancer, Shanghai, 200441, China.
FAU - Bao, Jinxia
AU  - Bao J
AD  - School of Medicine, Nanjing University, Nanjing, 210093, China.
FAU - Zhao, Xiaofang
AU  - Zhao X
AD  - Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical 
      College, Fudan University, Shanghai, 200032, China.
FAU - Zhao, Yan
AU  - Zhao Y
AD  - Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 
      200433, China.
FAU - Zong, Yali
AU  - Zong Y
AD  - Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 
      200433, China.
FAU - Zhang, Yani
AU  - Zhang Y
AD  - Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 
      200433, China.
FAU - Yang, Shuai
AU  - Yang S
AD  - Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical 
      College, Fudan University, Shanghai, 200032, China.
FAU - Qiu, Xinyao
AU  - Qiu X
AD  - Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical 
      College, Fudan University, Shanghai, 200032, China.
FAU - Shen, Siyun
AU  - Shen S
AD  - The International Cooperation Laboratory on Signal Transduction, Eastern 
      Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 
      200438, China.
AD  - National Center for Liver Cancer, Shanghai, 200441, China.
FAU - Wu, Rui
AU  - Wu R
AD  - Department of Biliary Surgery I, Eastern Hepatobiliary Surgery Hospital, Second 
      Military Medical University, Shanghai, 200438, China.
FAU - Wu, Tong
AU  - Wu T
AD  - The International Cooperation Laboratory on Signal Transduction, Eastern 
      Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 
      200438, China.
AD  - National Center for Liver Cancer, Shanghai, 200441, China.
FAU - Wang, Hongyang
AU  - Wang H
AD  - Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical 
      College, Fudan University, Shanghai, 200032, China.
AD  - The International Cooperation Laboratory on Signal Transduction, Eastern 
      Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 
      200438, China.
AD  - National Center for Liver Cancer, Shanghai, 200441, China.
FAU - Gao, Dong
AU  - Gao D
AD  - University of Chinese Academy of Sciences, Beijing, 100049, China.
AD  - State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular 
      Andrology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for 
      Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 
      200031, China.
AD  - Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 
      100101, China.
FAU - Wang, Peng
AU  - Wang P
AD  - School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, 
      China.
AD  - CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and 
      Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 
      Shanghai, 200031, China.
AD  - University of Chinese Academy of Sciences, Beijing, 100049, China.
FAU - Chen, Lei
AU  - Chen L
AUID- ORCID: 0000-0002-9380-9559
AD  - Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical 
      College, Fudan University, Shanghai, 200032, China.
AD  - National Center for Liver Cancer, Shanghai, 200441, China.
AD  - Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer 
      (SMMU), Ministry of Education, Shanghai, 200438, China.
AD  - Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, 200438, 
      China.
LA  - eng
GR  - U21A20376/National Natural Science Foundation of China/
GR  - 82102871/National Natural Science Foundation of China/
GR  - 81988101/National Natural Science Foundation of China/
GR  - 81903184/National Natural Science Foundation of China/
GR  - 81790633/National Natural Science Foundation of China/
GR  - 81830054/National Natural Science Foundation of China/
GR  - 2019-01-07-00-07-E00065/Innovation Program of Shanghai Municipal Education 
      Commission/
GR  - 21XD1404600/National Science Foundation of Shanghai/
GR  - 21JC1406600/National Science Foundation of Shanghai/
GR  - 22140901000/National Science Foundation of Shanghai/
GR  - 2020M671007/China Postdoctoral Science Foundation/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220605
PL  - Germany
TA  - Adv Sci (Weinh)
JT  - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
JID - 101664569
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - 0 (Peptides)
SB  - IM
MH  - Antigens, Neoplasm/genetics
MH  - Histocompatibility Antigens Class I
MH  - Humans
MH  - *Immune Checkpoint Inhibitors
MH  - *Neoplasms/therapy
MH  - Organoids
MH  - Peptides
PMC - PMC9353440
OTO - NOTNLM
OT  - TP53
OT  - immune checkpoint inhibitor
OT  - multiomics analysis
OT  - neoantigen
OT  - patient derived hepatobiliary tumor organoid
COIS- The authors declare no conflict of interest.
EDAT- 2022/06/07 06:00
MHDA- 2022/08/09 06:00
PMCR- 2022/06/05
CRDT- 2022/06/06 14:32
PHST- 2022/05/08 00:00 [revised]
PHST- 2021/12/15 00:00 [received]
PHST- 2022/06/07 06:00 [pubmed]
PHST- 2022/08/09 06:00 [medline]
PHST- 2022/06/06 14:32 [entrez]
PHST- 2022/06/05 00:00 [pmc-release]
AID - ADVS4178 [pii]
AID - 10.1002/advs.202105810 [doi]
PST - ppublish
SO  - Adv Sci (Weinh). 2022 Aug;9(22):e2105810. doi: 10.1002/advs.202105810. Epub 2022 
      Jun 5.