Abstract A001: Reshaping the immune microenvironment after temozolomide priming in metastatic colorectal cancer patients in ARETHUSA clinical trial
Notice bibliographique
Résumé
Abstract Mismatch repair (MMR) proficient (MMRp) tumors, known for their weak immune response, often exhibit limited effectiveness in immunotherapy. In contrast, responsive mismatch repair deficient (MMRd) tumors, characterized by heightened immune activity, show a stronger response to immune checkpoint blockade (ICB). In the ARETHUSA clinical trial (NCT03519412), we revealed that treatment with temozolomide (TMZ) can pharmacologically deactivate the MMR machinery, as indicated by mutational signature analysis and the emergence of MMR gene mutations. We focused our investigation on a subset of initially MMRp CRC patients who experienced sustained disease stabilization with ICB after receiving TMZ priming treatment. This treatment resulted in the emergence of an inactivating MSH6 mutation and the TMZ mutational signature. Additionally, TMZ treatment induced diverse genomic changes, leading to the identification of three distinct subtypes through analysis of blood and tissue samples. Notably, we observed a dose-dependent accumulation of mutations with a specific molecular signature visible at the clonal level (subtype B2) in 10% of patients, at the subclonal level (subtype B1) in 71% of patients, and the absence of these mutations (subtype A) in 19% of patients within our cohort of 21 patients. In conjunction with previous genetic findings, in this new study we performed an analysis of T-cell receptors (TCRs) in the tumor microenvironment following TMZ treatment. Our results revealed expanded clonotypes in tumors that exhibited a clonal increase in mutations following priming treatment. Furthermore, the diversity of TCRs within the immune infiltrate confirmed the categorization of tumors into three distinct classes based on Tumor Mutational Burden (TMB) and mutational signatures. We also established a significant linear correlation (p-value 0.0048) between the diversity of T-cells in the microenvironment and the number of mutations induced by TMZ. Based on these clinically-oriented preliminary findings, we propose that increasing the number of TMZ-induced mutations could enhance the likelihood of TMZ-driven neoantigens triggering clonal expansion of specific T-cell clonotypes within the tumor. Interestingly, the subset of TMZ-treated tumors displaying an acquired MSH6 mutation, TMZ mutational signature, and increased TMB not only achieved temporary disease stabilization with ICB but also exhibited clonal expansion of T-cells in the tumor microenvironment. These clinically relevant findings suggest that the inactivation of MMR achieved through TMZ priming has the potential to reshape the immune microenvironment modulating the immune response in metastatic colorectal cancer. Citation Format: Giovanni Crisafulli, Andrea Sartore-Bianchi, Luca Lazzari, Filippo Pietrantonio, Paolo Battuello, Alice Bartolini, Federica Di Nicolantonio, Silvia Marsoni, Salvatore Siena, Alberto Bardelli. Reshaping the immune microenvironment after temozolomide priming in metastatic colorectal cancer patients in ARETHUSA clinical trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A001.
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 | 0,002 | 0,001 |
| 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 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,000 | 0,001 |
| 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 ».