PMID- 38542184
OWN - NLM
STAT- MEDLINE
DCOM- 20240329
LR  - 20240506
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 25
IP  - 6
DP  - 2024 Mar 11
TI  - Gemcitabine Modulates HLA-I Regulation to Improve Tumor Antigen Presentation by 
      Pancreatic Cancer Cells.
LID - 10.3390/ijms25063211 [doi]
LID - 3211
AB  - Pancreatic cancer is a lethal disease, harboring a five-year overall survival 
      rate of only 13%. Current treatment approaches thus require modulation, with 
      attention shifting towards liberating the stalled efficacy of immunotherapies. 
      Select chemotherapy drugs which possess inherent immune-modifying behaviors could 
      revitalize immune activity against pancreatic tumors and potentiate 
      immunotherapeutic success. In this study, we characterized the influence of 
      gemcitabine, a chemotherapy drug approved for the treatment of pancreatic cancer, 
      on tumor antigen presentation by human leukocyte antigen class I (HLA-I). 
      Gemcitabine increased pancreatic cancer cells' HLA-I mRNA transcripts, total 
      protein, surface expression, and surface stability. Temperature-dependent assay 
      results indicated that the increased HLA-I stability may be due to reduced 
      binding of low affinity peptides. Mass spectrometry analysis confirmed changes in 
      the HLA-I-presented peptide pool post-treatment, and computational predictions 
      suggested improved affinity and immunogenicity of peptides displayed solely by 
      gemcitabine-treated cells. Most of the gemcitabine-exclusive peptides were 
      derived from unique source proteins, with a notable overrepresentation of 
      translation-related proteins. Gemcitabine also increased expression of select 
      immunoproteasome subunits, providing a plausible mechanism for its modulation of 
      the HLA-I-bound peptidome. Our work supports continued investigation of 
      immunotherapies, including peptide-based vaccines, to be used with gemcitabine as 
      new combination treatment modalities for pancreatic cancer.
FAU - Larson, Alaina C
AU  - Larson AC
AD  - Eppley Institute for Research in Cancer & Allied Diseases, Fred & Pamela Buffett 
      Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
FAU - Knoche, Shelby M
AU  - Knoche SM
AD  - Eppley Institute for Research in Cancer & Allied Diseases, Fred & Pamela Buffett 
      Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
FAU - Brumfield, Gabrielle L
AU  - Brumfield GL
AUID- ORCID: 0009-0003-3499-7531
AD  - Eppley Institute for Research in Cancer & Allied Diseases, Fred & Pamela Buffett 
      Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
FAU - Doty, Kenadie R
AU  - Doty KR
AD  - Eppley Institute for Research in Cancer & Allied Diseases, Fred & Pamela Buffett 
      Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
FAU - Gephart, Benjamin D
AU  - Gephart BD
AD  - Eppley Institute for Research in Cancer & Allied Diseases, Fred & Pamela Buffett 
      Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
FAU - Moore-Saufley, Promise R
AU  - Moore-Saufley PR
AD  - Departments of Psychology and Biology, University of Nebraska Omaha, Omaha, NE 
      68192, USA.
FAU - Solheim, Joyce C
AU  - Solheim JC
AD  - Eppley Institute for Research in Cancer & Allied Diseases, Fred & Pamela Buffett 
      Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
LA  - eng
GR  - U54 GM115458/GM/NIGMS NIH HHS/United States
GR  - R25 CA221777/NH/NIH HHS/United States
GR  - P30 CA036727/CA/NCI NIH HHS/United States
GR  - R25 CA221777/CA/NCI NIH HHS/United States
GR  - P30 CA036727/NH/NIH HHS/United States
GR  - T32 CA009476/CA/NCI NIH HHS/United States
GR  - T32 CA009476/NH/NIH HHS/United States
GR  - U54 GM115458/NH/NIH HHS/United States
PT  - Journal Article
DEP - 20240311
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Gemcitabine)
RN  - 0W860991D6 (Deoxycytidine)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Peptides)
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Pancreatic Hormones)
SB  - IM
MH  - Humans
MH  - *Gemcitabine
MH  - Deoxycytidine/therapeutic use
MH  - Antigen Presentation
MH  - *Pancreatic Neoplasms/metabolism
MH  - Histocompatibility Antigens Class I/genetics
MH  - Peptides
MH  - Antigens, Neoplasm/therapeutic use
MH  - Pancreatic Hormones
MH  - Cell Line, Tumor
PMC - PMC10970070
OTO - NOTNLM
OT  - antigen presentation
OT  - chemotherapy
OT  - gemcitabine
OT  - human leukocyte antigen class I
OT  - immunomodulatory
OT  - immunoproteasome
OT  - neoantigen
OT  - pancreatic cancer
OT  - peptide
COIS- The authors declare no conflicts of interest.
EDAT- 2024/03/28 06:45
MHDA- 2024/03/29 06:46
PMCR- 2024/03/11
CRDT- 2024/03/28 01:17
PHST- 2024/01/30 00:00 [received]
PHST- 2024/02/25 00:00 [revised]
PHST- 2024/03/04 00:00 [accepted]
PHST- 2024/03/29 06:46 [medline]
PHST- 2024/03/28 06:45 [pubmed]
PHST- 2024/03/28 01:17 [entrez]
PHST- 2024/03/11 00:00 [pmc-release]
AID - ijms25063211 [pii]
AID - ijms-25-03211 [pii]
AID - 10.3390/ijms25063211 [doi]
PST - epublish
SO  - Int J Mol Sci. 2024 Mar 11;25(6):3211. doi: 10.3390/ijms25063211.