Immune microenvironment and noncoding RNA shape early colorectal carcinogenesis in patients with premalignant lesions
(1) Morgand E (2) Van den Eynde M (3) Nguyen H (4) Batto AF (5) Mlecnik B (6) Baldin P (7) Majdi A (8) Fredriksen T (9) Lafontaine L (10) Bindea G (11) Mezine F (12) Shararah M (13) Vasaturo A (14) Hijazi A (15) Buttard B (16) Maby P (17) Ramos RN (18) Gragera P (19) Kirilovsky A (20) El Sissy C (21) Marliot F (22) Pags F (23) Vempalli FR (24) Hendrickx W (25) Masoodi T (26) Ceccarelli M (27) Bedognetti D (28) Galon J
Morgand et al. performed a retrospective, longitudinal study characterizing 258 pre-malignant colorectal lesions across discovery and validation cohorts. Patients were stratified based on polyps per year. Sequenced lesions shared few mutations, suggesting their sporadic and independent origin. Patients with the lowest polyp development rates exhibited lesions characterized by high immune cell infiltration and mature TLSs persisting from initial polyp onset to recurrent lesions. Such lesions showed increased expression of non-coding RNAs, which were associated with higher predicted immunogenicity and increased T cell density in tumor centers.
Contributed by Paula Hochman
(1) Morgand E (2) Van den Eynde M (3) Nguyen H (4) Batto AF (5) Mlecnik B (6) Baldin P (7) Majdi A (8) Fredriksen T (9) Lafontaine L (10) Bindea G (11) Mezine F (12) Shararah M (13) Vasaturo A (14) Hijazi A (15) Buttard B (16) Maby P (17) Ramos RN (18) Gragera P (19) Kirilovsky A (20) El Sissy C (21) Marliot F (22) Pags F (23) Vempalli FR (24) Hendrickx W (25) Masoodi T (26) Ceccarelli M (27) Bedognetti D (28) Galon J
Morgand et al. performed a retrospective, longitudinal study characterizing 258 pre-malignant colorectal lesions across discovery and validation cohorts. Patients were stratified based on polyps per year. Sequenced lesions shared few mutations, suggesting their sporadic and independent origin. Patients with the lowest polyp development rates exhibited lesions characterized by high immune cell infiltration and mature TLSs persisting from initial polyp onset to recurrent lesions. Such lesions showed increased expression of non-coding RNAs, which were associated with higher predicted immunogenicity and increased T cell density in tumor centers.
Contributed by Paula Hochman
ABSTRACT: Early cancer detection and prophylactic intervention remain the primary strategies for reducing colorectal carcinoma incidence and mortality. Although the immune microenvironment and tumor-associated antigens have been shown to play a pivotal role in carcinogenesis, the factors shaping immune dynamics during the premalignant phase remain poorly understood. In this study, we performed a comprehensive multimodal characterization of the immune microenvironment in 258 longitudinal premalignant colorectal lesions. Using a discovery cohort of 135 lesions from 26 patients stratified by low versus high polyp development rate, we identified distinct immune states associated with polyp burden. These findings were validated in an independent cohort of 123 lesions from 43 patients. Lesions from patients with low polyp development rates exhibited signatures of robust immune surveillance characterized by enhanced adaptive immune infiltration, including defined T cell subsets, and a higher prevalence of mature tertiary lymphoid structures compared with lesions from patients with high polyp frequency. These immune features were accompanied by increased expression of noncoding RNAs. These transcripts were predicted to encode noncanonical antigens with high MHC-I (major histocompatibility complex class I) binding affinity, potentially increasing lesion immunogenicity. We propose that early carcinogenesis is shaped by the immune microenvironment in association with noncoding RNAs, revealing potential early biomarkers in individuals at high risk of developing colorectal cancer.
Author Info:
(1) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers,
Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (2) Institut Roi Albert II, Department of Medical Oncology Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Universit Catholique de Louvain, 1200 Brussels, Belgium. (3) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (4) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (5) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (6) Department of Pathology, Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole GAEN) Universit Catholique de Louvain, 1200 Brussels, Belgium. (7) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (8) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (9) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (10) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (11) Universit Paris Cit, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, 75015 Paris, France. (12) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (13) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (14) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (15) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (16) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (17) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (18) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. (19) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. Assistance Publique-Hpitaux de Paris (AP-HP), Immunomonitoring Platform, Laboratory of Immunology, Georges Pompidou European Hospital, 75015 Paris, France. (20) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. Assistance Publique-Hpitaux de Paris (AP-HP), Immunomonitoring Platform, Laboratory of Immunology, Georges Pompidou European Hospital, 75015 Paris, France. (21) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. Assistance Publique-Hpitaux de Paris (AP-HP), Immunomonitoring Platform, Laboratory of Immunology, Georges Pompidou European Hospital, 75015 Paris, France. (22) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France. Assistance Publique-Hpitaux de Paris (AP-HP), Immunomonitoring Platform, Laboratory of Immunology, Georges Pompidou European Hospital, 75015 Paris, France. (23) Sidra Medicine, P.O. Box 26999, Doha, Qatar. (24) Sidra Medicine, P.O. Box 26999, Doha, Qatar. (25) Sidra Medicine, P.O. Box 26999, Doha, Qatar. (26) Sylvester Comprehensive Cancer Center and Department of Public Health Sciences, University of Miami, Miami, FL 33136, USA. (27) Sidra Medicine, P.O. Box 26999, Doha, Qatar. Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy. (28) INSERM, Laboratory of Integrative Cancer Immunology, F-75006 Paris, France. Equipe Labellise Ligue Contre le Cancer, F-75006 Paris, France. Centre de Recherche des Cordeliers, Sorbonne Universit, Universit Paris Cit, F-75006 Paris, France.
Citation: Sci Transl Med 2026 Jun 10 18:eaed2424 Epub06/10/2026
