302 Characterization of TIGIT and PVR expression in colorectal liver metastases
Notice bibliographique
Résumé
<h3>Background</h3> Metastatic colorectal cancer (CRC) is common and lethal and generally not responsive to current immunotherapies. We hypothesize that efficacious T cell-based immunotherapy can be developed for this malignancy, provided that immune checkpoints relevant to liver metastasis, the first site of disease progression, are targeted. Here, we characterized CRC liver metastases by RNAseq, FACS and in vitro functional assays to identify candidate immune checkpoints. <h3>Methods</h3> We performed deep RNAseq clustering and differential gene expression analysis on bulk RNA extracted from 52 mismatch repair gene proficient CRC liver metastases. By multiparameter FACS, we analyzed the expression of candidate immune checkpoints in cell suspensions derived from 18 liver metastases, matched non-tumoral livers, and pre-operative PBMCs. We evaluated IFN-γ (ELISA) secretion and tumor lysis (Incucyte) of tumor-infiltrating T lymphocytes (TILs) expanded from liver metastases stimulated by autologous cancer cells with or without monoclonal antibodies blocking candidate immune checkpoints. <h3>Results</h3> Out of 52 metastases, 21 (40.3%) clustered as immune reactive (IR) defined by concurrent high expression of transcripts related to antigen processing, immune cell lineage, immune checkpoints, interferon-gamma response, cytokines, and chemokines, whereas 25 (48.1%) were classified as non-IR. Of all inhibitory ligands assessed, PVR and PVRL2 had the highest expression, both in IR and non-IR metastases, and higher than PD-L1 and PD-L2 expression. The expression of corresponding receptors TIGIT and CD226 was significantly higher in IR compared to non-IR metastases, at absolute levels higher than PD-1. By FACS analysis, PVR and PVRL2 expression by tumor-infiltrating myeloid and tumor cells was higher than PD-L1 and PD-L2 expression. High PVR expression was also found in hepatocytes, liver macrophages and circulating monocytes in the same patients. In TILs, TIGIT was significantly overexpressed in activated CD4+CD25+ (74.8 ±3.0%) and CD8+CD25+ (68.7 ± 8.4%) compared to resting CD25neg T cells, an expression pattern that was not seen for PD-1 or in T cells infiltrating the liver or circulating in the blood. The majority of cancer cell lines derived from liver metastases expressed PVR, but low levels of PD-L1. TIL clones expanded from liver metastases expressed TIGIT at various levels inducible by TCR stimulation. Upon co-culture with autologous cancer cell lines, TIL clones were more lytic and secreted more IFN-γ in presence of anti-TIGIT blocking antibody. <h3>Conclusions</h3> By expression and functional data, the TIGIT/PVR immune suppressive axis appears as a biologically promising target for the development of immunotherapy in patients with CRC metastatic to the liver. <h3>Acknowledgements</h3> This work is supported by Bristol Myers Squibb and by the Quebec Cancer Consortium. A.B. holds a postdoctoral scholarship award from the Institut du cancer de Montréal. S.T. holds a Junior 2 clinical-scientist salary award from the Fond de recherche Santé-Québec. The University of Montreal Roger des Groseillers Research Chair in hepatopancreatobiliary surgical oncology supports the biobanking and clinicopathological database associated with this project. <h3>Ethics Approval</h3> Institutional review board approvals were obtain to conduct this project (16.262) and all patients provided informed consent to contribute to this project with biospecimens and clinicopathological data (09.237).
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».