PMID- 36341354
OWN - NLM
STAT- MEDLINE
DCOM- 20221108
LR  - 20221222
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 13
DP  - 2022
TI  - Effects of hypoxia on antigen presentation and T cell-based immune recognition of 
      HPV16-transformed cells.
PG  - 918528
LID - 10.3389/fimmu.2022.918528 [doi]
LID - 918528
AB  - Attempts to develop a therapeutic vaccine against human papillomavirus 
      (HPV)-induced malignancies have mostly not been clinically successful to date. 
      One reason may be the hypoxic microenvironment present in most tumors, including 
      cervical cancer. Hypoxia dysregulates the levels of human leukocyte antigen (HLA) 
      class I molecules in different tumor entities, impacts the function of cytotoxic 
      T cells, and leads to decreased protein levels of the oncoproteins E6 and E7 in 
      HPV-transformed cells. Therefore, we investigated the effect of hypoxia on the 
      presentation of HPV16 E6- and E7-derived epitopes in cervical cancer cells and 
      its effect on epitope-specific T cell cytotoxicity. Hypoxia induced 
      downregulation of E7 protein levels in all analyzed cell lines, as assessed by 
      Western blotting. However, contrary to previous reports, no perturbation of 
      antigen processing and presentation machinery (APM) components and HLA-A2 surface 
      expression upon hypoxia treatment was detected by mass spectrometry and flow 
      cytometry, respectively. Cytotoxicity assays performed in hypoxic conditions 
      showed differential effects on the specific killing of HPV16-positive cervical 
      cancer cells by epitope-specific CD8(+) T cell lines in a donor- and 
      peptide-specific manner. Effects of hypoxia on the expression of PD-L1 were ruled 
      out by flow cytometry analysis. Altogether, our results under hypoxia show a 
      decreased expression of E6 and E7, but an intact APM, and epitope- and 
      donor-dependent effects on T cell cytotoxicity towards HPV16-positive target 
      cells. This suggests that successful immunotherapies can be developed for hypoxic 
      HPV-induced cervical cancer, with careful choice of target epitopes, and ideally 
      in combination with hypoxia-alleviating measures.
CI  - Copyright (c) 2022 Mohan, Wellach, Ozerdem, Veits, Forster, Foehr, Bonsack and 
      Riemer.
FAU - Mohan, Nitya
AU  - Mohan N
AD  - Immunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), 
      Heidelberg, Germany.
AD  - Molecular Vaccine Design, German Center for Infection Research (DZIF), Partner 
      Site Heidelberg, Heidelberg, Germany.
AD  - Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
FAU - Wellach, Kathrin
AU  - Wellach K
AD  - Immunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), 
      Heidelberg, Germany.
AD  - Molecular Vaccine Design, German Center for Infection Research (DZIF), Partner 
      Site Heidelberg, Heidelberg, Germany.
AD  - Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
FAU - Ozerdem, Ceren
AU  - Ozerdem C
AD  - Immunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), 
      Heidelberg, Germany.
AD  - Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
FAU - Veits, Nisha
AU  - Veits N
AD  - Immunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), 
      Heidelberg, Germany.
AD  - Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
FAU - Forster, Jonas D
AU  - Forster JD
AD  - Immunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), 
      Heidelberg, Germany.
AD  - Molecular Vaccine Design, German Center for Infection Research (DZIF), Partner 
      Site Heidelberg, Heidelberg, Germany.
AD  - Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
FAU - Foehr, Sophia
AU  - Foehr S
AD  - Immunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), 
      Heidelberg, Germany.
AD  - Molecular Vaccine Design, German Center for Infection Research (DZIF), Partner 
      Site Heidelberg, Heidelberg, Germany.
FAU - Bonsack, Maria
AU  - Bonsack M
AD  - Immunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), 
      Heidelberg, Germany.
AD  - Molecular Vaccine Design, German Center for Infection Research (DZIF), Partner 
      Site Heidelberg, Heidelberg, Germany.
FAU - Riemer, Angelika B
AU  - Riemer AB
AD  - Immunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), 
      Heidelberg, Germany.
AD  - Molecular Vaccine Design, German Center for Infection Research (DZIF), Partner 
      Site Heidelberg, Heidelberg, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221021
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (Histocompatibility Antigens Class I)
SB  - IM
MH  - Female
MH  - Humans
MH  - Human papillomavirus 16
MH  - Antigen Presentation
MH  - *Uterine Cervical Neoplasms
MH  - *Papillomavirus Infections
MH  - Epitopes, T-Lymphocyte
MH  - Papillomaviridae
MH  - Histocompatibility Antigens Class I
MH  - Hypoxia
MH  - Tumor Microenvironment
PMC - PMC9634485
OTO - NOTNLM
OT  - Hypoxia
OT  - antigen processing and presentation machinery (APM)
OT  - cytotoxic T cells
OT  - human papillomavirus (HPV)
OT  - tumor microenvironment (TME)
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/11/08 06:00
MHDA- 2022/11/09 06:00
PMCR- 2022/01/01
CRDT- 2022/11/07 05:17
PHST- 2022/04/13 00:00 [received]
PHST- 2022/09/26 00:00 [accepted]
PHST- 2022/11/07 05:17 [entrez]
PHST- 2022/11/08 06:00 [pubmed]
PHST- 2022/11/09 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2022.918528 [doi]
PST - epublish
SO  - Front Immunol. 2022 Oct 21;13:918528. doi: 10.3389/fimmu.2022.918528. eCollection 
      2022.