PMID- 37857526
OWN - NLM
STAT- MEDLINE
DCOM- 20231023
LR  - 20231029
IS  - 2051-1426 (Electronic)
IS  - 2051-1426 (Linking)
VI  - 11
IP  - 10
DP  - 2023 Oct
TI  - Vaccination with post-translational modified, homocitrullinated peptides induces 
      CD8 T-cell responses that mediate antitumor immunity.
LID - 10.1136/jitc-2023-006966 [doi]
LID - e006966
AB  - BACKGROUND: Post-translational modification of proteins has the potential to 
      alter the ability of T cells to recognize major histocompatibility complex (MHC) 
      class -I and class-II restricted antigens, thereby resulting in altered immune 
      responses. One such modification is carbamylation (homocitrullination) that 
      results in the formation of homocitrulline (Hcit) residues in a non-enzymatic 
      reaction of cyanate with the lysine residues in the polypeptide chain. 
      Homocitrullination occurs in the tumor microenvironment and CD4-mediated immune 
      responses to Hcit epitopes can target stressed tumor cells and provide a potent 
      antitumor response in mouse models. METHODS: Homocitrullinated peptides were 
      identified and assessed in vitro for HLA-A2 binding and in vivo in human 
      leukocyte antigen (HLA) transgenic mouse models for immunogenicity. CD8 responses 
      were assessed in vitro for cytotoxicity and in vivo tumor therapy. Human tumor 
      samples were analyzed by targeted mass spectrometry for presence of 
      homocitrullinated peptides. RESULTS: Homocitrullinated peptides from aldolase and 
      cytokeratin were identified, that stimulated CD8-mediated responses in vivo. 
      Modified peptides showed enhanced binding to HLA-A2 compared with the native 
      sequences and immunization of HLA-A2 transgenic mice generated high avidity 
      modification specific CD8 responses that killed peptide expressing target cells. 
      Importantly, in vivo the homocitrullinated aldolase specific response was 
      associated with efficient CD8 dependent antitumor therapy of the aggressive 
      murine B16 tumor model indicating that this epitope is naturally presented in the 
      tumor. In addition, the homocitrullinated aldolase epitope was also detected in 
      human tumor samples. CONCLUSION: This is the first evidence that 
      homocitrullinated peptides can be processed and presented via MHC-I and targeted 
      for tumor therapy. Thus, Hcit-specific CD8 T-cell responses have potential in the 
      development of future anticancer therapy.
CI  - (c) Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Shah, Sabaria
AU  - Shah S
AD  - Scancell Ltd, Nottingham, UK.
FAU - Cook, Katherine W
AU  - Cook KW
AUID- ORCID: 0000-0002-7277-6700
AD  - Scancell Ltd, Nottingham, UK.
FAU - Symonds, Peter
AU  - Symonds P
AD  - Scancell Ltd, Nottingham, UK.
FAU - Weisser, Juliane
AU  - Weisser J
AD  - Proteome Science R&D GmbH und Co, Frankfurt am Main, Hessen, Germany.
FAU - Skinner, Anne
AU  - Skinner A
AD  - Scancell Ltd, Nottingham, UK.
FAU - Al Omari, Abdullah
AU  - Al Omari A
AD  - Scancell Ltd, Nottingham, UK.
FAU - Paston, Samantha J
AU  - Paston SJ
AD  - Scancell Ltd, Nottingham, UK.
FAU - Pike, Ian
AU  - Pike I
AD  - Proteome Science R&D GmbH und Co, Frankfurt am Main, Hessen, Germany.
FAU - Durrant, Lindy G
AU  - Durrant LG
AD  - Scancell Ltd, Nottingham, UK.
AD  - University of Nottingham, Nottingham, UK.
FAU - Brentville, Victoria A
AU  - Brentville VA
AUID- ORCID: 0000-0003-2000-5629
AD  - Scancell Ltd, Nottingham, UK VictoriaBrentville@scancell.co.uk.
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 (HLA-A2 Antigen)
RN  - 0 (Histocompatibility Antigens Class II)
RN  - 0 (Peptides)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Epitopes)
RN  - EC 4.1.2.- (Aldehyde-Lyases)
SB  - IM
MH  - Mice
MH  - Humans
MH  - Animals
MH  - *HLA-A2 Antigen
MH  - *CD8-Positive T-Lymphocytes
MH  - Histocompatibility Antigens Class II/metabolism
MH  - Vaccination
MH  - Mice, Transgenic
MH  - Peptides
MH  - Histocompatibility Antigens Class I
MH  - Epitopes
MH  - Protein Processing, Post-Translational
MH  - Aldehyde-Lyases/metabolism
PMC - PMC10603355
OTO - NOTNLM
OT  - CD8-positive T-lymphocytes
OT  - antigens
OT  - immunogenicity, vaccine
OT  - immunotherapy
COIS- Competing interests: KWC, VAB and LGD have ownership interests in a patent. LGD 
      is a director and shareholder in Scancell Ltd. SS, KWC, PS, AS, AAO, SJP and VAB 
      are employees of Scancell Ltd. JW and IP are employees of Proteome Sciences.
EDAT- 2023/10/20 00:43
MHDA- 2023/10/23 01:18
PMCR- 2023/10/19
CRDT- 2023/10/19 21:53
PHST- 2023/09/13 00:00 [accepted]
PHST- 2023/10/23 01:18 [medline]
PHST- 2023/10/20 00:43 [pubmed]
PHST- 2023/10/19 21:53 [entrez]
PHST- 2023/10/19 00:00 [pmc-release]
AID - jitc-2023-006966 [pii]
AID - 10.1136/jitc-2023-006966 [doi]
PST - ppublish
SO  - J Immunother Cancer. 2023 Oct;11(10):e006966. doi: 10.1136/jitc-2023-006966.