Interrogating the immune landscape of microsatellite stable <scp>RAS</scp> ‐mutated colon cancer

To explore the immune microenvironment of RAS-mutated (RASmt) microsatellite stable (MSS) colon cancer (CC), we retrospectively performed whole exome sequencing, RNA sequencing, and robust digital pathology analyses and studied immune markers in a cohort of 161 patients treated with standard-of-care therapies with early stage disease (both fresh frozen and formalin-fixed paraffin-embedded [FFPE] samples) or 121 patients with metastatic setting (primary tumor FFPE samples). Only a small proportion of cases exhibited a highly infiltrated immune microenvironment, with a strong association between Immunoscore<sup>®</sup> (IS)-high (13% of the samples) and Tumor Lymphocytes Infiltrating Score (TuLIS)-high scores (25% of the samples). Immunoscore Immune-Checkpoint (ISIC)-high tumors (52% of the samples) shared a similar microenvironment composition to IS-high and TuLIS-like high tumors and displayed higher mutational burdens than ISIC-low tumors. In conclusion, a substantial proportion of MSS RASmt CCs exhibit high ISIC scores, meriting evaluation in prospective trials of immunotherapy-based combination regimens.

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Publication Details

Journal
Molecular Oncology
Published
2026-02-24
DOI
https://doi.org/10.1002/1878-0261.70225
Primary Topic
Genetic factors in colorectal cancer
Type
article
Field-Weighted Citation Impact
0.00

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article

Interrogating the immune landscape of microsatellite stable RAS ‐mutated colon cancer

Maxime Meylan, Nadja M. Meindl‐Beinker, Florent Petitprez, Ian S. Miller et al.
Molecular Oncology
Genetic factors in colorectal cancer
article

Interrogating the immune landscape of microsatellite stable RAS ‐mutated colon cancer

Maxime Meylan, Nadja M. Meindl‐Beinker, Florent Petitprez, Ian S. Miller, Andrea Ruíz, BR Bird, Lars Scheuer, Marvin Lim, Zak Kinsella, Kathleen Bennett, Georg Bolz, Raquel Pérez-López, Lisa Stack, H. M. Prehn Jochen, Tom Venken, Anguraj Sadanandam, Órla Casey, Jacques Fieschi, Aoife A. Nolan, I. Arijs, Gift Nyamundanda, Frank A. Lincoln, Joern Lewin, ALEXANDER KEL, Joachim Behringer, Deborah A. McNamara, P. Nuciforo, Annette T. Byrne, Mary O’Reilly, Jonathan Briody, Bart Ghesquière, Julie Meilleroux, Joaquín Arribas, R. Dienstmann, David Matallanas, Hari Didapati Bahawa Kultur Ps, Keith Egan, Elena M Elez, Darran J O'Connor, C. Muñoz Santos, Adrian Lärkeryd, Dirk Fey, Josep Tabernero, Catherine Sautès-Fridman, Walter Kolch, Verena Murphy, P. G. Morris, Janick Selves, D. Lambrechts, Florence Monville, Matthias Ebert, Livio Trusolino, Lucia Moloney, Enrique Arenas, Alice O'Farrell, Eduardo García-Galea, Raquel Comas-Navarro, Maciej Milewski
article en

Abstract

To explore the immune microenvironment of RAS-mutated (RASmt) microsatellite stable (MSS) colon cancer (CC), we retrospectively performed whole exome sequencing, RNA sequencing, and robust digital pathology analyses and studied immune markers in a cohort of 161 patients treated with standard-of-care therapies with early stage disease (both fresh frozen and formalin-fixed paraffin-embedded [FFPE] samples) or 121 patients with metastatic setting (primary tumor FFPE samples). Only a small proportion of cases exhibited a highly infiltrated immune microenvironment, with a strong association between Immunoscore<sup>®</sup> (IS)-high (13% of the samples) and Tumor Lymphocytes Infiltrating Score (TuLIS)-high scores (25% of the samples). Immunoscore Immune-Checkpoint (ISIC)-high tumors (52% of the samples) shared a similar microenvironment composition to IS-high and TuLIS-like high tumors and displayed higher mutational burdens than ISIC-low tumors. In conclusion, a substantial proportion of MSS RASmt CCs exhibit high ISIC scores, meriting evaluation in prospective trials of immunotherapy-based combination regimens.

Molecular Oncology
University College Dublin (IE), Universitat de Vic - Universitat Central de Catalunya (ES), Hebron University (PS), Universitat Autònoma de Barcelona (ES), Université Toulouse III - Paul Sabatier (FR), Royal College of Surgeons in Ireland (IE), Institute of Cancer Research (GB), Inserm (FR), Université Paris Cité (FR), Heidelberg University (DE), Bon Secours Hospital Cork (IE), Beaumont Hospital (IE), University Hospital Heidelberg (DE), Tallaght University Hospital (IE), Sorbonne Université (FR), Institut d'Investigació Biomédica de Bellvitge (ES), Centre de Recherche des Cordeliers (FR), VIB-KU Leuven Center for Cancer Biology (BE), Institut universitaire du cancer de Toulouse Oncopole (FR), Netherlands Metabolomics Centre (NL), Vall d'Hebron Institut de Recerca (ES), Cancer Trials Ireland (IE), Center for Human Genetics (US), Institut Català d'Oncologia (ES), St. Vincent's University Hospital (IE), Veracyte (United States) (US), GeneXplain (Germany) (DE), European Molecular Biology Laboratory (DE), Praxis für Hämatologie und Onkologie (DE), Candiolo Cancer Institute (IT), University Medical Centre Mannheim (DE), University of Turin (IT), Epigenomics (Germany) (DE)
European Commission, Ministero della Salute, Associazione Italiana per la Ricerca sul Cancro
Good health and well-being
Openalex Percentile: Top 44%
Genetic factors in colorectal cancer
DOIOpen Access PDFOpenAlex
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