TY - JOUR
T1 - Transcriptomic Signatures of MSI-High Metastatic Colorectal Cancer Predict Efficacy of Immune Checkpoint Inhibitors
AU - Gallois, Claire
AU - Landi, Matteo
AU - Taieb, Julien
AU - Sroussi, Marine
AU - Saberzadeh-Ardestani, Bahar
AU - Cazelles, Antoine
AU - Lonardi, Sara
AU - Bergamo, Francesca
AU - Intini, Rossana
AU - Maddalena, Giulia
AU - Pietrantonio, Filippo
AU - Corti, Francesca
AU - Ambrosini, Margherita
AU - Martinetti, Antonia
AU - Germani, Marco Maria
AU - Boccaccio, Chiara
AU - Vetere, Guglielmo
AU - Mouillet-Richard, Sophie
AU - de Reynies, Aurelien
AU - Sinicrope, Frank A.
AU - Cremolini, Chiara
AU - Laurent-Puig, Pierre
N1 - Publisher Copyright:
© 2023 The Authors; Published by the American Association for Cancer Research.
PY - 2023/9/15
Y1 - 2023/9/15
N2 - Purpose: 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. Experimental Design: In two cohorts of patients with MSI mCRC treated with ICI (exploratory, N ¼ 103; validation, N ¼ 35), 30 RNA sequencing was performed from primary tumors. Previously described single-cell transcriptomic signatures of tumor microenvironment (TME) were analyzed. Results: 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 ¼ 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 ¼ 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. Conclusions: 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.
AB - Purpose: 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. Experimental Design: In two cohorts of patients with MSI mCRC treated with ICI (exploratory, N ¼ 103; validation, N ¼ 35), 30 RNA sequencing was performed from primary tumors. Previously described single-cell transcriptomic signatures of tumor microenvironment (TME) were analyzed. Results: 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 ¼ 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 ¼ 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. Conclusions: 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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U2 - 10.1158/1078-0432.CCR-22-3964
DO - 10.1158/1078-0432.CCR-22-3964
M3 - Article
C2 - 37439810
AN - SCOPUS:85171393487
SN - 1078-0432
VL - 29
SP - 3771
EP - 3778
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 18
ER -