FAK suppresses antigen processing and presentation to promote immune evasion in pancreatic cancer.
antigen presentation
antigen processing
cell adhesion molecules
immune response
pancreatic cancer
Journal
Gut
ISSN: 1468-3288
Titre abrégé: Gut
Pays: England
ID NLM: 2985108R
Informations de publication
Date de publication:
07 Dec 2023
07 Dec 2023
Historique:
received:
24
05
2022
accepted:
19
03
2023
pubmed:
29
3
2023
medline:
29
3
2023
entrez:
28
3
2023
Statut:
epublish
Résumé
Immunotherapy for the treatment of pancreatic ductal adenocarcinoma (PDAC) has shown limited efficacy. Poor CD8 T-cell infiltration, low neoantigen load and a highly immunosuppressive tumour microenvironment contribute to this lack of response. Here, we aimed to further investigate the immunoregulatory function of focal adhesion kinase (FAK) in PDAC, with specific emphasis on regulation of the type-II interferon response that is critical in promoting T-cell tumour recognition and effective immunosurveillance. We combined CRISPR, proteogenomics and transcriptomics with mechanistic experiments using a Kras Loss of PDAC cell-intrinsic FAK signalling promotes expression of the immunoproteasome and Major Histocompatibility Complex class-I (MHC-I), resulting in increased antigen diversity and antigen presentation by FAK-/- PDAC cells. Regulation of the immunoproteasome by FAK is a critical determinant of this response, optimising the physicochemical properties of the peptide repertoire for high affinity binding to MHC-I. Expression of these pathways can be further amplified in a STAT1-dependent manner via co-depletion of FAK and STAT3, resulting in extensive infiltration of tumour-reactive CD8 T-cells and further restraint of tumour growth. FAK-dependent regulation of antigen processing and presentation is conserved between mouse and human PDAC, but is lost in cells/tumours with an extreme squamous phenotype. Therapies aimed at FAK degradation may unlock additional therapeutic benefit for the treatment of PDAC through increasing antigen diversity and promoting antigen presentation.
Identifiants
pubmed: 36977556
pii: gutjnl-2022-327927
doi: 10.1136/gutjnl-2022-327927
pmc: PMC10715489
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
131-155Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
Références
Gut. 2022 Apr;71(4):766-777
pubmed: 33846140
Clin Cancer Res. 2017 Jun 15;23(12):3129-3138
pubmed: 28007776
Bioinformatics. 2014 Oct;30(19):2811-2
pubmed: 24930139
J Immunother Cancer. 2021 Feb;9(2):
pubmed: 33637602
Gastroenterology. 2021 Jan;160(1):362-377.e13
pubmed: 33039466
Bioinformatics. 2005 Aug 15;21(16):3439-40
pubmed: 16082012
Nat Methods. 2020 Sep;17(9):869-870
pubmed: 32669682
Elife. 2019 May 28;8:
pubmed: 31134896
PLoS Comput Biol. 2019 Mar 5;15(3):e1006701
pubmed: 30835723
Nat Commun. 2020 Feb 14;11(1):896
pubmed: 32060274
Front Oncol. 2021 Jul 15;11:688377
pubmed: 34336673
Elife. 2020 Jan 21;9:
pubmed: 31959281
Nat Biotechnol. 2012 Oct;30(10):918-20
pubmed: 23051804
BMC Bioinformatics. 2018 Nov 6;19(1):404
pubmed: 30400809
Bioinformatics. 2012 Dec 15;28(24):3211-7
pubmed: 23071270
Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20212-7
pubmed: 24277834
Nat Rev Immunol. 2022 Mar;22(3):158-172
pubmed: 34155388
Nat Commun. 2014 Oct 31;5:5277
pubmed: 25358478
J Clin Invest. 2004 Aug;114(4):551-9
pubmed: 15314692
Nat Commun. 2021 Jun 7;12(1):3414
pubmed: 34099731
Nat Rev Cancer. 2021 May;21(5):313-324
pubmed: 33731845
Genome Biol. 2014;15(12):550
pubmed: 25516281
Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):E1555-64
pubmed: 26929325
JCI Insight. 2016 Sep 8;1(14):
pubmed: 27642636
Nature. 2017 Nov 23;551(7681):512-516
pubmed: 29132146
Mol Cancer Ther. 2011 Nov;10(11):2135-45
pubmed: 21903606
F1000Res. 2016 Jun 29;5:1542
pubmed: 28232861
Nat Rev Immunol. 2006 Nov;6(11):836-48
pubmed: 17063185
Front Microbiol. 2015 Jan 29;6:21
pubmed: 25688236
Bioinformatics. 2018 Sep 1;34(17):i884-i890
pubmed: 30423086
Nat Med. 2016 Aug;22(8):851-60
pubmed: 27376576
Oncoimmunology. 2017 Sep 14;7(1):e1364828
pubmed: 29296515
J Mol Biol. 1982 May 5;157(1):105-32
pubmed: 7108955
Nature. 2016 Mar 3;531(7592):47-52
pubmed: 26909576
Immunity. 2018 Jul 17;49(1):178-193.e7
pubmed: 29958801
Cancer Res. 2014 Jun 1;74(11):2913-21
pubmed: 24840647
JAMA Oncol. 2017 Jun 01;3(6):774-783
pubmed: 27768182
Nat Genet. 2015 Oct;47(10):1168-78
pubmed: 26343385
Bioinformatics. 2016 Sep 15;32(18):2847-9
pubmed: 27207943
F1000Res. 2015 Dec 30;4:1521
pubmed: 26925227
J Am Chem Soc. 2018 Dec 12;140(49):17019-17026
pubmed: 30444612
Nat Rev Immunol. 2012 Dec;12(12):813-20
pubmed: 23175229
Gastroenterology. 2019 May;156(7):2056-2072
pubmed: 30660727
J Immunother Cancer. 2016 Mar 15;4:14
pubmed: 26981244
Nat Med. 2011 Apr;17(4):500-3
pubmed: 21460848
Br J Cancer. 2022 Nov;127(10):1893-1905
pubmed: 36138073
J Natl Cancer Inst. 2012 Feb 8;104(3):228-39
pubmed: 22247021
Nature. 1991 May 23;351(6324):290-6
pubmed: 1709722
Oncoimmunology. 2016 Mar 28;5(6):e1151593
pubmed: 27471621
ACS Med Chem Lett. 2019 Oct 22;11(10):1855-1862
pubmed: 33062164
Proteomics. 2019 Feb;19(3):e1800280
pubmed: 30537264
BMC Bioinformatics. 2013 Jan 16;14:7
pubmed: 23323831
Nat Rev Immunol. 2005 May;5(5):375-86
pubmed: 15864272
JAKSTAT. 2012 Apr 1;1(2):65-72
pubmed: 24058752
Nucleic Acids Res. 2016 May 5;44(8):e71
pubmed: 26704973
PLoS Genet. 2015 Jul 09;11(7):e1005375
pubmed: 26158850
J Immunol. 2017 Nov 1;199(9):3360-3368
pubmed: 28978689
Cancer Res. 2007 Jul 15;67(14):6981-6
pubmed: 17638910
Cancer Cell. 2017 Aug 14;32(2):185-203.e13
pubmed: 28810144
Sci Rep. 2016 Oct 20;6:35848
pubmed: 27762323
Acta Oncol. 2016 Sep - Oct;55(9-10):1158-1160
pubmed: 27551890
J Natl Cancer Inst. 2013 Aug 21;105(16):1172-87
pubmed: 23852952
Lancet Gastroenterol Hepatol. 2019 Dec;4(12):895-896
pubmed: 31648975
Mol Cancer Ther. 2020 Feb;19(2):637-649
pubmed: 31784455
Nucleic Acids Res. 2020 Nov 4;48(19):e113
pubmed: 32997146
Cell. 2021 Dec 9;184(25):6119-6137.e26
pubmed: 34890551
Hepatobiliary Pancreat Dis Int. 2014 Aug;13(4):371-80
pubmed: 25100121
Nat Protoc. 2013 Nov;8(11):2281-2308
pubmed: 24157548
Nat Methods. 2017 Apr;14(4):417-419
pubmed: 28263959
J Exp Med. 1998 Jan 5;187(1):97-104
pubmed: 9419215
Pancreatology. 2019 Mar;19(2):340-345
pubmed: 30685120
Cell. 2015 Sep 24;163(1):160-73
pubmed: 26406376
Blood. 2007 Dec 15;110(13):4341-50
pubmed: 17855630
Trends Cancer. 2017 Oct;3(10):726-741
pubmed: 28958390
Cell Rep. 2020 May 12;31(6):107625
pubmed: 32402285