American Association for Cancer Research
ccr-22-3964_supplemental_figure_5_suppfs5.docx (80.53 kB)

Supplemental Figure 5 from Transcriptomic Signatures of MSI-High Metastatic Colorectal Cancer Predict Efficacy of Immune Checkpoint Inhibitors

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journal contribution
posted on 2023-09-15, 08:22 authored by Claire Gallois, Matteo Landi, Julien Taieb, Marine Sroussi, Bahar Saberzadeh-Ardestani, Antoine Cazelles, Sara Lonardi, Francesca Bergamo, Rossana Intini, Giulia Maddalena, Filippo Pietrantonio, Francesca Corti, Margherita Ambrosini, Antonia Martinetti, Marco Maria Germani, Chiara Boccaccio, Guglielmo Vetere, Sophie Mouillet-Richard, Aurélien de Reynies, Frank A. Sinicrope, Chiara Cremolini, Pierre Laurent-Puig

Kaplan Meier curves for progression-free survival according to the three unsupervised clusters in the validation cohort


Institut National Du Cancer (INCa)

Institut National de la Santé et de la Recherche Médicale (Inserm)

Labex Immuno-Oncology (ImmunoOnco)



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.

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