Anti-PD-1 in Combination With Trametinib Suppresses Tumor Growth and Improves Survival of Intrahepatic Cholangiocarcinoma in Mice.
Animals
Bile Duct Neoplasms
/ drug therapy
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Cholangiocarcinoma
/ drug therapy
Drug Synergism
Female
High-Throughput Nucleotide Sequencing
Humans
Immune Checkpoint Inhibitors
/ administration & dosage
Mice
Programmed Cell Death 1 Receptor
/ antagonists & inhibitors
Pyridones
/ administration & dosage
Pyrimidinones
/ administration & dosage
Exome Sequencing
Xenograft Model Antitumor Assays
Anti–PD-1 Monoclonal Antibody
Intrahepatic Cholangiocarcinoma
Trametinib
Journal
Cellular and molecular gastroenterology and hepatology
ISSN: 2352-345X
Titre abrégé: Cell Mol Gastroenterol Hepatol
Pays: United States
ID NLM: 101648302
Informations de publication
Date de publication:
2021
2021
Historique:
received:
17
01
2021
revised:
14
05
2021
accepted:
15
05
2021
pubmed:
26
5
2021
medline:
12
3
2022
entrez:
25
5
2021
Statut:
ppublish
Résumé
Intrahepatic cholangiocarcinoma (iCCA) accounts for a fraction of primary liver cancers but has a 5-year survival rate of only 10%. Immune checkpoint inhibitors are effective in treating many solid cancers, but immune checkpoint inhibitor monotherapy has no clear benefit in iCCA. Mitogen-activated kinase (MEK) inhibitors, such as trametinib, have shown promising results in preclinical studies for iCCA by inhibiting cell proliferation and modifying the tumor microenvironment. This study aimed to show the potential benefit of combining trametinib with anti-programmed cell death protein 1 (PD-1) therapy in different iCCA mouse models. Here, we assessed the in vitro cytotoxicity of trametinib in mouse (SB1 and LD-1) and human (EGI-1) cholangiocarcinoma cell lines. We examined the efficacy of single-agent trametinib, anti-PD-1, and a combination of both in subcutaneous, orthotopic, and plasmid-induced iCCA mouse models. Flow cytometry analysis was used to elucidate changes in the tumor immune microenvironment upon treatment. Whole-exome sequencing (WES) was performed on the SB1 tumor cell line to correlate this preclinical model with iCCAs in patients. Trametinib reduced tumor cell growth of SB1, LD-1, and EGI-1 tumor cells in vitro. Trametinib treatment led to up-regulation of major histocompatibility complex (MHC-I) and programmed cell death ligand 1 (PD-L-1) (programmed cell death ligand 1) on tumor cells in vitro. The combination of trametinib and anti-PD-1 reduced tumor burden in several iCCA tumor models and improved survival in SB1 tumor-bearing mice compared with either agent alone. Immunoprofiling of tumor-bearing mice showed an increase of hepatic effector memory CD8 Altogether, our study shows that trametinib improves the immunogenicity of tumor cells by up-regulating MHC-I surface expression. The combination with anti-PD-1 results in optimal treatment efficacy for iCCA. WES of SB1 cells suggests that KRAS wild-type iCCAs also respond to this combination therapy.
Sections du résumé
BACKGROUND & AIMS
Intrahepatic cholangiocarcinoma (iCCA) accounts for a fraction of primary liver cancers but has a 5-year survival rate of only 10%. Immune checkpoint inhibitors are effective in treating many solid cancers, but immune checkpoint inhibitor monotherapy has no clear benefit in iCCA. Mitogen-activated kinase (MEK) inhibitors, such as trametinib, have shown promising results in preclinical studies for iCCA by inhibiting cell proliferation and modifying the tumor microenvironment. This study aimed to show the potential benefit of combining trametinib with anti-programmed cell death protein 1 (PD-1) therapy in different iCCA mouse models.
METHODS
Here, we assessed the in vitro cytotoxicity of trametinib in mouse (SB1 and LD-1) and human (EGI-1) cholangiocarcinoma cell lines. We examined the efficacy of single-agent trametinib, anti-PD-1, and a combination of both in subcutaneous, orthotopic, and plasmid-induced iCCA mouse models. Flow cytometry analysis was used to elucidate changes in the tumor immune microenvironment upon treatment. Whole-exome sequencing (WES) was performed on the SB1 tumor cell line to correlate this preclinical model with iCCAs in patients.
RESULTS
Trametinib reduced tumor cell growth of SB1, LD-1, and EGI-1 tumor cells in vitro. Trametinib treatment led to up-regulation of major histocompatibility complex (MHC-I) and programmed cell death ligand 1 (PD-L-1) (programmed cell death ligand 1) on tumor cells in vitro. The combination of trametinib and anti-PD-1 reduced tumor burden in several iCCA tumor models and improved survival in SB1 tumor-bearing mice compared with either agent alone. Immunoprofiling of tumor-bearing mice showed an increase of hepatic effector memory CD8
CONCLUSIONS
Altogether, our study shows that trametinib improves the immunogenicity of tumor cells by up-regulating MHC-I surface expression. The combination with anti-PD-1 results in optimal treatment efficacy for iCCA. WES of SB1 cells suggests that KRAS wild-type iCCAs also respond to this combination therapy.
Identifiants
pubmed: 34033968
pii: S2352-345X(21)00100-4
doi: 10.1016/j.jcmgh.2021.05.011
pmc: PMC8413239
pii:
doi:
Substances chimiques
Immune Checkpoint Inhibitors
0
PDCD1 protein, human
0
Programmed Cell Death 1 Receptor
0
Pyridones
0
Pyrimidinones
0
trametinib
33E86K87QN
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1166-1178Subventions
Organisme : Intramural NIH HHS
ID : ZIA BC011345
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Références
J Hepatol. 2014 Jun;60(6):1268-89
pubmed: 24681130
Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4164-9
pubmed: 15016911
JHEP Rep. 2019 Jul 10;1(4):297-311
pubmed: 32039381
BMC Bioinformatics. 2010 Jul 02;11:367
pubmed: 20598126
BMC Med Genomics. 2014 Dec 03;7:64
pubmed: 25466818
Hepatology. 2016 Nov;64(5):1785-1791
pubmed: 27177447
N Engl J Med. 2020 May 14;382(20):1894-1905
pubmed: 32402160
Methods Protoc. 2018 Jun 04;1(2):
pubmed: 31164564
Hepatol Res. 2016 Jun;46(7):669-77
pubmed: 26508039
Cancer Immunol Res. 2014 Apr;2(4):351-60
pubmed: 24764582
Curr Protoc Bioinformatics. 2013;43:11.10.1-11.10.33
pubmed: 25431634
Nat Genet. 2015 Sep;47(9):1003-10
pubmed: 26258846
Cell Death Dis. 2019 Feb 11;10(2):120
pubmed: 30741922
Lancet. 2014 Jun 21;383(9935):2168-79
pubmed: 24581682
J Clin Invest. 2012 Aug;122(8):2911-5
pubmed: 22797301
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Genome Res. 2018 Nov;28(11):1747-1756
pubmed: 30341162
Cancer Discov. 2021 May;11(5):1248-1267
pubmed: 33323397
Genome Biol. 2016 Jun 06;17(1):122
pubmed: 27268795
Genome Res. 2010 Sep;20(9):1297-303
pubmed: 20644199
J Hepatol. 2020 Feb;72(2):364-377
pubmed: 31954498
Clin Cancer Res. 2016 Apr 15;22(8):1845-55
pubmed: 27084738
Oncologist. 2019 Feb;24(Suppl 1):S3-S10
pubmed: 30819826
Front Immunol. 2017 Dec 04;8:1597
pubmed: 29255458
JAMA Oncol. 2020 Jun 1;6(6):888-894
pubmed: 32352498
Nat Med. 2019 May;25(5):861
pubmed: 30918364
Oncol Res Treat. 2016;39(10):635-642
pubmed: 27710977
Cell Mol Immunol. 2021 Jan;18(1):112-127
pubmed: 33235387
Cancer Sci. 2018 Jan;109(1):215-224
pubmed: 29121415
Genome Med. 2018 Apr 25;10(1):33
pubmed: 29695279
J Biol Response Mod. 1985 Aug;4(4):391-5
pubmed: 3928826
Nucleic Acids Res. 2016 May 5;44(8):e71
pubmed: 26704973
Int J Mol Sci. 2020 Apr 05;21(7):
pubmed: 32260561
Oncotarget. 2017 Dec 22;9(5):5892-5905
pubmed: 29464042
Ann Surg Oncol. 2008 Feb;15(2):600-8
pubmed: 17987347
Expert Opin Investig Drugs. 2018 Jan;27(1):17-30
pubmed: 29216787
N Engl J Med. 1999 Oct 28;341(18):1368-78
pubmed: 10536130
J Hepatol. 2019 Jul;71(1):104-114
pubmed: 30910538