Transcriptomic Signatures of MSI-High Metastatic Colorectal Cancer Predict Efficacy of Immune Checkpoint Inhibitors.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 09 2023
15 09 2023
Historique:
received:
18
01
2023
revised:
10
05
2023
accepted:
10
07
2023
medline:
18
9
2023
pubmed:
13
7
2023
entrez:
13
7
2023
Statut:
ppublish
Résumé
Microsatellite instability (MSI) is currently the only predictive biomarker of efficacy of immune checkpoint inhibitors (ICI) in metastatic colorectal cancers (mCRC). However, 10% to 40% of patients with MSI mCRC will experience a primary resistance to ICI. In two cohorts of patients with MSI mCRC treated with ICI (exploratory, N = 103; validation, N = 35), 3' RNA sequencing was performed from primary tumors. Previously described single-cell transcriptomic signatures of tumor microenvironment (TME) were analyzed. In the exploratory cohort, the unsupervised clustering allowed the identification of three clusters of tumors with distinct transcriptional profiles: cluster A ("stromalHIGH-proliferationLOW"), cluster B ("stromalHIGH-proliferationMED"), and cluster C ("stromalLOW-proliferationHIGH"), with an enrichment of patients progressing at first disease assessment under ICI in cluster A (30% vs. 12% in cluster B and 8.1% in cluster C; P = 0.074). Progression-free survival (PFS) was also significantly shorter in patients belonging to cluster A, compared with clusters B or C (P < 0.001) with 2-year PFS rates of 33.5%, 80.5%, and 78.3%, respectively. In multivariate analysis, PFS was still significantly longer in patients belonging to cluster B [HR, 0.19; 95% confidence interval (CI), 0.08-0.45; P < 0.001] and cluster C (HR, 0.25; 95% CI, 0.10-0.59; P = 0.02), compared with patients belonging to cluster A. The association of this clustering with PFS under ICI was confirmed in the validation cohort. PFS related to non-ICI-based regimens was not significantly different according to cluster. This unsupervised transcriptomic classification identified three groups of MSI mCRCs with different compositions of TME cells and proliferative capacities of TME/tumor cells. The "stromalHIGH-proliferationLOW" cluster is associated with a poorer prognosis with ICI treatment.
Identifiants
pubmed: 37439810
pii: 727788
doi: 10.1158/1078-0432.CCR-22-3964
pmc: PMC10502457
doi:
Substances chimiques
Immune Checkpoint Inhibitors
0
Biomarkers
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3771-3778Informations de copyright
©2023 The Authors; Published by the American Association for Cancer Research.
Références
Nat Med. 2021 Feb;27(2):212-224
pubmed: 33574607
Eur J Cancer. 2022 Nov;175:136-157
pubmed: 36115290
N Engl J Med. 2020 Dec 3;383(23):2207-2218
pubmed: 33264544
N Engl J Med. 2015 Jun 25;372(26):2509-20
pubmed: 26028255
Eur J Cancer. 2022 Sep;172:171-181
pubmed: 35777274
J Clin Oncol. 2018 Mar 10;36(8):773-779
pubmed: 29355075
Lancet Oncol. 2014 Jul;15(8):862-73
pubmed: 24928083
BMC Bioinformatics. 2013 Jan 16;14:7
pubmed: 23323831
Lancet Oncol. 2017 Sep;18(9):1182-1191
pubmed: 28734759
Cancer Discov. 2020 Sep;10(9):1330-1351
pubmed: 32434947
NAR Genom Bioinform. 2020 Sep;2(3):lqaa078
pubmed: 33015620
Cancer Cell. 2021 Jun 14;39(6):845-865.e7
pubmed: 34019806
Nat Rev Immunol. 2020 Jan;20(1):25-39
pubmed: 31570880
Sci Transl Med. 2022 Nov 9;14(670):eabo3605
pubmed: 36350989
JAMA Netw Open. 2023 Feb 1;6(2):e230400
pubmed: 36811859
Ther Adv Med Oncol. 2018 Jan 18;10:1758834017749748
pubmed: 29383037
Cell. 2021 Sep 2;184(18):4734-4752.e20
pubmed: 34450029
Nat Med. 2020 Apr;26(4):566-576
pubmed: 32251400
Nat Commun. 2022 Nov 28;13(1):7316
pubmed: 36443332
Clin Cancer Res. 2023 Apr 3;29(7):1183-1193
pubmed: 36445399
Cells. 2021 Oct 28;10(11):
pubmed: 34831157
Nucleic Acids Res. 2019 May 7;47(8):e47
pubmed: 30783653
Cancer Immunol Immunother. 2012 Jul;61(7):1019-31
pubmed: 22146893
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Lancet. 2016 Apr 30;387(10030):1837-46
pubmed: 26970723
N Engl J Med. 2022 Jun 23;386(25):2363-2376
pubmed: 35660797
Science. 2017 Jul 28;357(6349):409-413
pubmed: 28596308