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
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

3771-3778

Informations de copyright

©2023 The Authors; Published by the American Association for Cancer Research.

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Auteurs

Claire Gallois (C)

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Paris, France.
Institut du Cancer Paris CARPEM, AP-HP Centre, Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris, France.

Matteo Landi (M)

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.

Julien Taieb (J)

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Paris, France.
Institut du Cancer Paris CARPEM, AP-HP Centre, Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris, France.

Marine Sroussi (M)

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Paris, France.
Institut Chimie Biologie Innovation - Laboratoire de BioChimie, ESPCI, UMR8231 CNRS, Université PSL, Paris, France.

Bahar Saberzadeh-Ardestani (B)

Gastrointestinal Research Unit, Departments of Medicine and Medical Oncology, Mayo Clinic, Rochester, Minnesota.

Antoine Cazelles (A)

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Paris, France.

Sara Lonardi (S)

Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IRCCS, Padova, Italy.

Francesca Bergamo (F)

Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IRCCS, Padova, Italy.

Rossana Intini (R)

Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IRCCS, Padova, Italy.

Giulia Maddalena (G)

Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IRCCS, Padova, Italy.

Filippo Pietrantonio (F)

Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Francesca Corti (F)

Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Margherita Ambrosini (M)

Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Antonia Martinetti (A)

Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Marco Maria Germani (MM)

Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.

Chiara Boccaccio (C)

Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.

Guglielmo Vetere (G)

Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.

Sophie Mouillet-Richard (S)

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Paris, France.

Aurélien de Reynies (A)

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Paris, France.

Frank A Sinicrope (FA)

Gastrointestinal Research Unit, Departments of Medicine and Medical Oncology, Mayo Clinic, Rochester, Minnesota.

Chiara Cremolini (C)

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.

Pierre Laurent-Puig (P)

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Paris, France.
Institut du Cancer Paris CARPEM, APHP.Centre, Department of Biology, Hôpital Européen Georges Pompidou, Paris, France.

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