Article Dans Une Revue European Journal of Cancer Année : 2026

From clusters to clinic: An 8-gene signature combined with mucinous component stratifies benefit of anti-CTLA-4 addition to anti-PD-1 in dMMR/MSI-H metastatic colorectal cancer

Résumé

Background: Around 15-50% of patients with dMMR/MSI-H metastatic colorectal cancer (mCRC) experience primary and secondary resistance to immune checkpoint inhibitors (ICI). We previously described three transcriptomic clusters (A, B, C) linked to progression-free survival (PFS), with cluster A ("StromalHIGH - ProliferationLOW") associated with the shortest PFS. Here we combine gene signature and mucinous phenotype to predict the benefit from anti-CTLA-4 plus anti-PD-1. Methods: We used 3'RNA-sequencing data from pre-treatment samples of two independent cohorts of patients with dMMR/MSI-H mCRC treated with anti-PD-1 ±anti-LAG-3 ("Mono") or anti-PD-1 +anti-CTLA-4 ("Combo"). A rank-based k-Top Scoring Pairs (k-TSP) classifier was trained in Cohort 1 (103 patients) to predict assignment to Cluster A versus B/C and validated in Cohort 2 (87 patients). Patients receiving an anti-PD-L1 and with ECOG ≥ 2 were excluded. We defined a composite stratum crossing Clusterk-TSP (A vs B/C) with mucinous component (present vs absent). Results: Cluster A was enriched for mucinous tumors and had shorter PFS in both cohorts. The k-TSP selected four gene pairs predictive of Cluster A (YPEL2 >H2AZ1, H6PD>COX7A2, STAT5B>SNRPE, ZHX3 >TRAPPC4) and was validated in Cohort 2 with 68.1% balanced accuracy. In the pooled population (163 patients), the composite stratum × treatment interaction improved model fit (likelihood-ratio p ≈ 0.04). Patients with Clusterk-TSP A + mucinous (25/163, 15.3%) derived advantage from Combo versus Mono: adjusted 24-month PFS 72.2% vs 13.8% (HR 0.10, 95% CI 0.02-0.39; p < 0.001). Conclusions: An 8-Gene signature combined with mucinous component identifies a subgroup that preferentially benefits from anti-PD-1 +CTLA-4, warranting prospective validation to guide regimen selection in dMMR/MSI-H mCRC.

Domaines

Fichier principal
Vignette du fichier
1-s2.0-S0959804926005113-main.pdf (1023.92 Ko) Télécharger le fichier
Origine Publication financée par une institution
licence

Dates et versions

hal-05614636 , version 1 (12-05-2026)

Licence

Identifiants

Citer

Margherita Ambrosini, Claire Gallois, Annalice Gandini, Aurélie Lecanu, Emily Alouani, et al.. From clusters to clinic: An 8-gene signature combined with mucinous component stratifies benefit of anti-CTLA-4 addition to anti-PD-1 in dMMR/MSI-H metastatic colorectal cancer. European Journal of Cancer, 2026, 239, pp.116731. ⟨10.1016/j.ejca.2026.116731⟩. ⟨hal-05614636⟩
0 Consultations
0 Téléchargements

Altmetric

Partager

  • More