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Supplemental Figure 2 from Transcriptomic Signatures of MSI-High Metastatic Colorectal Cancer Predict Efficacy of Immune Checkpoint Inhibitors

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posted on 2023-08-08, 13:00 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 unsupervised clusters and the line of immune checkpoint inhibitor

Funding

Institut National Du Cancer (INCa)

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

Labex Immuno-Oncology (ImmunoOnco)

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ARTICLE ABSTRACT

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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