Protein citrullination as a source of cancer neoantigens.
antigens
autoimmunity
biomarkers
humoral
immunity
tumor
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
accepted:
06
04
2021
entrez:
11
6
2021
pubmed:
12
6
2021
medline:
12
1
2022
Statut:
ppublish
Résumé
Citrulline post-translational modification of proteins is mediated by protein arginine deiminase (PADI) family members and has been associated with autoimmune diseases. The role of PADI-citrullinome in immune response in cancer has not been evaluated. We hypothesized that PADI-mediated citrullinome is a source of neoantigens in cancer that induces immune response. Protein expression of PADI family members was evaluated in 196 cancer cell lines by means of indepth proteomic profiling. Gene expression was assessed using messenger RNA data sets from The Cancer Genome Atlas. Immunohistochemical analysis of PADI2 and peptidyl-citrulline was performed using breast cancer tissue sections. Citrullinated 12-34-mer peptides in the putative Major Histocompatibility Complex-II (MHC-II) binding range were profiled in breast cancer cell lines to investigate the relationship between protein citrullination and antigen presentation. We further evaluated immunoglobulin-bound citrullinome by mass spectrometry using 156 patients with breast cancer and 113 cancer-free controls. Proteomic and gene expression analyses revealed PADI2 to be highly expressed in several cancer types including breast cancer. Immunohistochemical analysis of 422 breast tumor tissues revealed increased expression of PADI2 in ER- tumors (p<0.0001); PADI2 protein expression was positively correlated (p<0.0001) with peptidyl-citrulline staining. PADI2 expression exhibited strong positive correlations with a B cell immune signature and with MHC-II-bound citrullinated peptides. Increased circulating citrullinated antigen-antibody complexes occurred among newly diagnosed breast cancer cases relative to controls (p=0.0012). An immune response associated with citrullinome is a rich source of neoantigens in breast cancer with a potential for diagnostic and therapeutic applications.
Sections du résumé
BACKGROUND
Citrulline post-translational modification of proteins is mediated by protein arginine deiminase (PADI) family members and has been associated with autoimmune diseases. The role of PADI-citrullinome in immune response in cancer has not been evaluated. We hypothesized that PADI-mediated citrullinome is a source of neoantigens in cancer that induces immune response.
METHODS
Protein expression of PADI family members was evaluated in 196 cancer cell lines by means of indepth proteomic profiling. Gene expression was assessed using messenger RNA data sets from The Cancer Genome Atlas. Immunohistochemical analysis of PADI2 and peptidyl-citrulline was performed using breast cancer tissue sections. Citrullinated 12-34-mer peptides in the putative Major Histocompatibility Complex-II (MHC-II) binding range were profiled in breast cancer cell lines to investigate the relationship between protein citrullination and antigen presentation. We further evaluated immunoglobulin-bound citrullinome by mass spectrometry using 156 patients with breast cancer and 113 cancer-free controls.
RESULTS
Proteomic and gene expression analyses revealed PADI2 to be highly expressed in several cancer types including breast cancer. Immunohistochemical analysis of 422 breast tumor tissues revealed increased expression of PADI2 in ER- tumors (p<0.0001); PADI2 protein expression was positively correlated (p<0.0001) with peptidyl-citrulline staining. PADI2 expression exhibited strong positive correlations with a B cell immune signature and with MHC-II-bound citrullinated peptides. Increased circulating citrullinated antigen-antibody complexes occurred among newly diagnosed breast cancer cases relative to controls (p=0.0012).
CONCLUSIONS
An immune response associated with citrullinome is a rich source of neoantigens in breast cancer with a potential for diagnostic and therapeutic applications.
Identifiants
pubmed: 34112737
pii: jitc-2021-002549
doi: 10.1136/jitc-2021-002549
pmc: PMC8194337
pii:
doi:
Substances chimiques
Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : U01 CA141539
Pays : United States
Informations de copyright
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
Références
Cancer Res. 2019 Apr 1;79(7):1274-1284
pubmed: 30894374
Cancer Res. 2010 Jul 15;70(14):5788-96
pubmed: 20587526
Cancer Res. 2009 Feb 1;69(3):728-30
pubmed: 19155298
J Rheumatol. 1983 Aug;10(4):558-62
pubmed: 6352937
BMC Bioinformatics. 2007 Jul 04;8:238
pubmed: 17608956
Arthritis Rheum. 1984 Aug;27(8):922-8
pubmed: 6380505
Curr Drug Targets. 2015;16(7):700-10
pubmed: 25642720
Neoplasia. 2004 Jan-Feb;6(1):1-6
pubmed: 15068665
Cancer Res. 2016 Feb 1;76(3):548-60
pubmed: 26719533
Nat Rev Immunol. 2017 Jan;17(1):60-75
pubmed: 27916980
Breast. 2018 Feb;37:196-199
pubmed: 28162837
J Biol Chem. 2018 Mar 2;293(9):3252-3253
pubmed: 29500270
Nat Rev Cancer. 2007 Jul;7(7):519-30
pubmed: 17585332
J Immunol. 1958 Apr;80(4):324-9
pubmed: 13539376
Cancer Res. 2015 Aug 15;75(16):3246-54
pubmed: 26088128
PLoS One. 2015 Mar 31;10(3):e0121460
pubmed: 25826333
Nat Rev Rheumatol. 2011 Jun 07;7(7):391-8
pubmed: 21647203
Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):E1555-64
pubmed: 26929325
Oncogene. 2010 May 27;29(21):3153-62
pubmed: 20190809
NPJ Precis Oncol. 2019 Apr 2;3:10
pubmed: 30963111
Bioinformatics. 2014 Feb 15;30(4):523-30
pubmed: 24336805
Cancer Res. 2016 Oct 1;76(19):5597-5601
pubmed: 27634765
Biomark Insights. 2006;1:175-183
pubmed: 18769604
PLoS One. 2009 Nov 19;4(11):e7916
pubmed: 19936259
Proteomics. 2014 Dec;14(23-24):2750-9
pubmed: 25331784
Nat Med. 2018 May;24(5):541-550
pubmed: 29686425
Cancer. 2018 May 15;124(10):2086-2103
pubmed: 29424936
Crit Rev Oncol Hematol. 2018 Jul;127:42-49
pubmed: 29891110
Arthritis Rheum. 2008 Oct;58(10):3009-19
pubmed: 18821669
Cancer Res. 2013 Mar 1;73(5):1502-13
pubmed: 23269276
J Natl Cancer Inst. 2020 Jun 1;112(6):607-616
pubmed: 31503278
Arthritis Rheum. 2010 Jan;62(1):117-25
pubmed: 20039411
Nat Commun. 2019 Jan 16;10(1):254
pubmed: 30651550
Methods. 2015 Jun 15;81:34-40
pubmed: 25794949
Immunology. 2018 Jul;154(3):394-406
pubmed: 29315598
Ann Oncol. 2020 Aug;31(8):1011-1020
pubmed: 32387455
Nat Rev Rheumatol. 2018 Mar;14(3):157-169
pubmed: 29416134
Immunity. 2013 Oct 17;39(4):782-95
pubmed: 24138885
Nature. 2019 Oct;574(7780):696-701
pubmed: 31645760
Proc Natl Acad Sci U S A. 2013 Jul 16;110(29):11851-6
pubmed: 23818587
Nat Commun. 2012 Feb 14;3:676
pubmed: 22334079
Clin Immunol Immunopathol. 1981 Mar;18(3):425-30
pubmed: 7018769
J Biol Chem. 2011 May 13;286(19):17069-78
pubmed: 21454715
Sci Signal. 2013 Apr 02;6(269):pl1
pubmed: 23550210
Science. 2004 Oct 8;306(5694):279-83
pubmed: 15345777
Nat Commun. 2017 Aug 4;8(1):199
pubmed: 28775315
Arthritis Res Ther. 2005;7(6):R1421-9
pubmed: 16277695
J Clin Invest. 1998 Jan 1;101(1):273-81
pubmed: 9421490
Oncoimmunology. 2017 Nov 6;7(2):e1390642
pubmed: 29308319
Nature. 2012 Apr 18;486(7403):346-52
pubmed: 22522925