Immunologic constant of rejection signature is prognostic in soft-tissue sarcoma and refines the CINSARC signature.
gene expression profiling
sarcoma
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:
01 2022
01 2022
Historique:
accepted:
01
11
2021
entrez:
12
1
2022
pubmed:
13
1
2022
medline:
17
3
2022
Statut:
ppublish
Résumé
Soft-tissue sarcomas (STSs) are heterogeneous and aggressive tumors, with high metastatic risk. The immunologic constant of rejection (ICR) 20-gene signature is a signature of cytotoxic immune response. We hypothesized that ICR might improve the prognostic assessment of early-stage STS. We retrospectively applied ICR to 1455 non-metastatic STS and searched for correlations between ICR classes and clinicopathological and biological variables, including metastasis-free survival (MFS). Thirty-four per cent of tumors were classified as ICR1, 27% ICR2, 24% ICR3, and 15% ICR4. These classes were associated with patients' age, pathological type, and tumor depth, and an enrichment from ICR1 to ICR4 of quantitative/qualitative scores of immune response. ICR1 class was associated with a 59% increased risk of metastatic relapse when compared with ICR2-4 class. In multivariate analysis, ICR classification remained associated with MFS, as well as pathological type and Complexity Index in Sarcomas (CINSARC) classification, suggesting independent prognostic value. A prognostic clinicogenomic model, including the three variables, was built in a learning set (n=339) and validated in an independent set (n=339), showing greater prognostic precision than each variable alone or in doublet. Finally, connectivity mapping analysis identified drug classes potentially able to reverse the expression profile of poor-prognosis tumors, such as chemotherapy and targeted therapies. ICR signature is independently associated with postoperative MFS in early-stage STS, independently from other prognostic features, including CINSARC. We built a robust prognostic clinicogenomic model integrating ICR, CINSARC, and pathological type, and suggested differential vulnerability of each prognostic group to different systemic therapies.
Sections du résumé
BACKGROUND
Soft-tissue sarcomas (STSs) are heterogeneous and aggressive tumors, with high metastatic risk. The immunologic constant of rejection (ICR) 20-gene signature is a signature of cytotoxic immune response. We hypothesized that ICR might improve the prognostic assessment of early-stage STS.
METHODS
We retrospectively applied ICR to 1455 non-metastatic STS and searched for correlations between ICR classes and clinicopathological and biological variables, including metastasis-free survival (MFS).
RESULTS
Thirty-four per cent of tumors were classified as ICR1, 27% ICR2, 24% ICR3, and 15% ICR4. These classes were associated with patients' age, pathological type, and tumor depth, and an enrichment from ICR1 to ICR4 of quantitative/qualitative scores of immune response. ICR1 class was associated with a 59% increased risk of metastatic relapse when compared with ICR2-4 class. In multivariate analysis, ICR classification remained associated with MFS, as well as pathological type and Complexity Index in Sarcomas (CINSARC) classification, suggesting independent prognostic value. A prognostic clinicogenomic model, including the three variables, was built in a learning set (n=339) and validated in an independent set (n=339), showing greater prognostic precision than each variable alone or in doublet. Finally, connectivity mapping analysis identified drug classes potentially able to reverse the expression profile of poor-prognosis tumors, such as chemotherapy and targeted therapies.
CONCLUSION
ICR signature is independently associated with postoperative MFS in early-stage STS, independently from other prognostic features, including CINSARC. We built a robust prognostic clinicogenomic model integrating ICR, CINSARC, and pathological type, and suggested differential vulnerability of each prognostic group to different systemic therapies.
Identifiants
pubmed: 35017155
pii: jitc-2021-003687
doi: 10.1136/jitc-2021-003687
pmc: PMC8753443
pii:
doi:
Substances chimiques
Biomarkers, Tumor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© Author(s) (or their employer(s)) 2022. 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
J Transl Med. 2020 Sep 1;18(1):337
pubmed: 32873319
Lancet Oncol. 2001 Nov;2(11):674-82
pubmed: 11902538
Oncoimmunology. 2017 Feb 6;6(2):e1253654
pubmed: 28344865
Nat Med. 2010 Jul;16(7):781-7
pubmed: 20581836
Am J Clin Oncol. 2011 Feb;34(1):82-6
pubmed: 23781555
Genome Biol. 2007;8(8):R157
pubmed: 17683518
PLoS One. 2011 Jan 27;6(1):e14611
pubmed: 21298041
Br J Cancer. 2018 Nov;119(11):1383-1391
pubmed: 30353048
Mod Pathol. 2007 Jul;20(7):749-59
pubmed: 17464315
J Clin Invest. 2017 Aug 1;127(8):2930-2940
pubmed: 28650338
Br J Cancer. 2015 Feb 3;112(3):547-55
pubmed: 25562433
Ann Oncol. 2018 Feb 1;29(2):459-465
pubmed: 29069276
Cancer. 2011 Jan 15;117(2):380-9
pubmed: 20818650
Clin Cancer Res. 2015 Aug 1;21(15):3501-11
pubmed: 25896974
Nature. 2020 Jan;577(7791):556-560
pubmed: 31942077
J Immunother Cancer. 2020 Oct;8(2):
pubmed: 33028693
J Immunother Cancer. 2020 Apr;8(1):
pubmed: 32376723
BMC Cancer. 2021 Feb 8;21(1):144
pubmed: 33557781
Cell. 2015 Jan 15;160(1-2):48-61
pubmed: 25594174
Oncotarget. 2015 May 10;6(13):11139-49
pubmed: 25871477
Genome Biol. 2005;6(9):R76
pubmed: 16168083
J Pathol. 2011 Jan;223(1):64-71
pubmed: 21125665
NPJ Precis Oncol. 2021 Mar 5;5(1):17
pubmed: 33674685
JAMA Oncol. 2017 Nov 1;3(11):1529-1537
pubmed: 28687838
BMC Genomics. 2007 Mar 14;8:73
pubmed: 17359542
Cell. 2017 Nov 2;171(4):950-965.e28
pubmed: 29100075
Clin Cancer Res. 2008 Mar 1;14(5):1423-30
pubmed: 18316565
Lancet Oncol. 2016 Dec;17(12):1732-1742
pubmed: 27751846
J Clin Oncol. 1997 Jan;15(1):350-62
pubmed: 8996162
PLoS Biol. 2005 Jun;3(6):e187
pubmed: 15869330
Front Genet. 2021 Feb 01;12:620705
pubmed: 33597971
Sci Rep. 2019 Apr 8;9(1):5759
pubmed: 30962488
Mol Cancer Ther. 2015 Feb;14(2):395-406
pubmed: 25519700
Br J Cancer. 2016 Oct 25;115(9):1096-1104
pubmed: 27701385
Cancer Res. 2005 Oct 15;65(20):9226-35
pubmed: 16230383
EBioMedicine. 2020 Dec;62:103131
pubmed: 33254023
Ann Oncol. 2014 Sep;25 Suppl 3:iii102-12
pubmed: 25210080
J Clin Oncol. 2009 Mar 10;27(8):1160-7
pubmed: 19204204
Ann Oncol. 2018 Oct 1;29(Suppl 4):iv51-iv67
pubmed: 29846498
Cancers (Basel). 2021 Jan 19;13(2):
pubmed: 33478080
Cancer Res. 2004 Oct 15;64(20):7201-4
pubmed: 15492233
J Clin Oncol. 2021 Feb 20;39(6):557-564
pubmed: 33306425
Nat Commun. 2020 Dec 17;11(1):6410
pubmed: 33335088
Oncogene. 2010 Feb 11;29(6):845-54
pubmed: 19901961
Lancet. 2002 Apr 13;359(9314):1301-7
pubmed: 11965276
Ann Oncol. 2018 Aug 1;29(8):1828-1835
pubmed: 29860427
Cancer Lett. 2014 Dec 1;355(1):70-5
pubmed: 25218596
Cancer. 2012 Sep 1;118(17):4235-43
pubmed: 22252777
Ann Oncol. 2019 Feb 1;30(2):342-343
pubmed: 30535178
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Cancer Res. 2011 Apr 1;71(7):2697-705
pubmed: 21335544
Cancers (Basel). 2021 Jan 20;13(3):
pubmed: 33498238
J Pathol. 2010 Jul;221(3):300-7
pubmed: 20527023
Immunity. 2013 Jul 25;39(1):11-26
pubmed: 23890060
Cancers (Basel). 2020 Oct 20;12(10):
pubmed: 33092134
Oncotarget. 2017 Dec 12;9(3):3946-3955
pubmed: 29423096
Immunity. 2013 Oct 17;39(4):782-95
pubmed: 24138885
Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):6994-9
pubmed: 20335537
J Clin Oncol. 2020 Nov 1;38(31):3638-3651
pubmed: 32897827
Nat Genet. 2010 Aug;42(8):715-21
pubmed: 20601955
Clin Oncol (R Coll Radiol). 2015 Oct;27(10):547-60
pubmed: 26282471
Am J Pathol. 2011 Jul;179(1):37-45
pubmed: 21703392
Oncoimmunology. 2017 Feb 8;6(3):e1278100
pubmed: 28405501
Cancer Res. 2005 Jul 1;65(13):5881-9
pubmed: 15994966
Oncoimmunology. 2020 Jul 12;9(1):1792036
pubmed: 32923153
Cancer Treat Rev. 2017 Sep;59:33-45
pubmed: 28732326
Mol Cancer. 2011 Jul 21;10:86
pubmed: 21777462
Genome Biol. 2013 Dec 17;14(12):r137
pubmed: 24345474
Int J Mol Sci. 2020 Apr 24;21(8):
pubmed: 32344731