Identification of intratumoral and peripheral T-cell receptor (TCR) repertoire features associated with acquired (Ar) and primary (Pr) resistance to immune checkpoint inhibitors (ICI).
Notice bibliographique
Résumé
59 Background: Our understanding of the mechanisms of Pr vs Ar to ICI is limited. T-cells are the main driver of ICI response. Therefore, interrogation of intratumoral and peripheral TCR repertoire could expand our comprehension of T-cell mediated factors underlying Pr and Ar to ICI. Methods: The Immune Resistance Interrogation Study (NCT04243720) is a prospective study to comprehensively characterize cancers with Pr vs Ar to ICI (Genta et. al., ASCO 2021). We conducted TCRβ capture and sequencing (CapTCR-seq) on paired tumors and blood samples collected from solid tumor patients (pts) at the time of progression on ICI. Tumor and peripheral TCR diversities were calculated for each pt. Grouping Lymphocyte Interactions by Paratope Hotspots (GLIPHII) was used to investigate the potential antigen specificities of intratumoral T-cells. Pt-derived TCRs were pooled with TCRs from a public database with known antigen specificities (TCRdb). GLIPHII grouped pt-derived and external TCRs with similar CDR3s (hypervariable TCR domains) in clusters. The clusters were then converted into a network model representing unique TCRs as nodes. The number of connections between each pt-derived TCR and similar TCRs from TCRdb was defined as node degree. Comparisons between groups were done using Mann Whitney U Test. Results: As of February 2023, 75 pts (45 Pr/30 Ar) were enrolled. CapTCR-Seq in blood and tumor samples was completed in 13 pts (7Pr/6Ar) with the following characteristics: median age 57 years (26-77), 8 male (62%), 8 melanoma (62%), 4 HNSCC (31%), and 1 GE-junction (7%). 5 pts received PD-1/PD-L1 inhibitor monotherapy (38%), 8 pts ICl-based combinations (62%). No significant differences in intratumoral (10.3 [1.3-34.2] vs 15.2 [6.6-32.4] p=0.29) and peripheral (145.5 [65.3- 521.9] vs 136.0 [35.1-474.4] p=0.53) Shannon diversities were observed between Pr and Ar. Twelve of 13 (92%) pts had at least 1 intratumoral TCR clustered with TCRdb derived TCRs. A higher median of node degree was observed in non-melanoma tumors (5.5 [2-12] vs 2.0 [1-4] p=0.03). A trend towards a higher median of node degree was reported in Ar vs Pr (5.5 [1-12] vs 2.0 [1-4] p=0 .07 ). Some of the GLIPHll-identified clusters contained TCRs derived from multiple Ar pts. Conclusions: lntratumoral TCRs from non-melanoma and Ar pts had a higher node degree, indicating similarity with a larger number of external TCRs. The difference between Pr and Ar was not significant, potentially due to the small sample size. Similar TCRs belonging to the same GLIPHll-identified clusters were shared among multiple Ar pts. If confirmed in a larger dataset, these findings might suggest the existence of a set of intratumoral exhausted T-cells shared by multiple pts contributing to Ar but not to Pr. Pt accrual, sample collection and analysis are ongoing. Additional data will be presented.
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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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 ».