Abstract PO-078: Tissue-resident memory CD8+ T cells correlate with anti-PD-1 response in head and neck cancer and expand upon cDC1 activation in tumor-draining lymph nodes to overcome PD-1 resistance
Notice bibliographique
Résumé
Abstract Introduction: Tumor infiltrating tissue-resident memory CD8+ T (TRM) cells correlate with immunotherapy response against several solid tumor types. Recent data from neoadjuvant immunotherapy studies highlight CD8+ TRM cells as early responders in head and neck squamous carcinoma (HNSCC). Here, we defined anti-tumor CD8+ TRM cell representation in neoadjuvant anti-PD1 clinical trial HNSCC tumors and examined their development in anti-PD1 responsive and resistant HNSCC mouse models. Methods: CD8+ CD103+ TRM cells were quantified using CODEX (CO-detection by inDEXing) in tumor tissue microarray cores from 28 HNSCC patients treated with neoadjuvant anti-PD1 on a previously reported clinical trial (NCT02296684). Anti-PD1 sensitive MOC1 and isogenic anti-PD1 resistant MOC1-esc1 cells were engineered to express ovalbumin derived SIINFEKL peptide (OVA). OVA-specific CD8+ TRM induction and activation from endogenous T cells and following OT-1 adoptive transfer was evaluated in orthotopic (buccal) MOC1/MOC1esc1-OVA tumor bearing mice by ELISA and flow cytometry employing SIINFEKL-H2Kbdextramers. In vitro OVA-directed T cell activity was evaluated using co-culture of OT-1 T cells and MOC1/MOC1OVA/MOC1esc1OVA cells, OVA peptide, or IL-2. OT-1 CD8+ T cells were transferred into MOC1OVA or MOC1-esc1OVA-bearing mice and the dynamics of TRM development were evaluated using flow cytometry. Conventional Dendritic cells 1 (cDC1s) from tumor-draining lymph nodes (TDLNs) were cocultured with OT-1 cells and evaluated for antigen-specific TRM development. Results: CD8+ CD103+ TRM cells were more frequent in baseline tumors that developed pathological tumor response following neoadjuvant pembrolizumab compared to baseline nonresponding tumors (p=0.011). In mouse orthotopic models, MOC1-esc1OVA cells maintained in vivo PD-1 resistance despite eliciting SIINFEKL dextramer+ antigen-specific T cells in the tumors that expanded in response to PD-1 blockade. Further characterization of these tumor antigen specific T cells showed that compared to MOC1OVA, MOC1-esc1OVA had reduced CD69 and CD103 expression (MOC1OVA, Average 17.55% (14.1-19.4%); MOC1-esc1OVA, Average 11.84% (9.42-15.8%); p=0.025) and reduced response to SIINFEKL restimulation (MOC1OVA, Average 1093.3 pg/mL (860.6-1240.9 pg/mL); MOC1-esc1OVA, Average 533.3 pg/mL (254.5-749.0 pg/mL); p=0.006). A time course analysis in vivo showed that OVA-specific TRM cells were generated in TDLN and migrated into tumor. Compared to MOC1-OVA, MOC1-esc1OVA TDLN cDC1s had reduced CD40 expression and fewer TRM cells. Anti-CD40 blocking monoclonal antibodies reduced OVA-specific TRM cells in MOC1OVA while CD40 agonist antibodies increased antitumor TRMs and reduced PD1-resistant tumor growth compared to the control IgG groups. Conclusion: These findings highlight TRM CD8_+ T cells as a correlate of PD-1 blockade response in HNSCC patient tissues and mouse models and delineate cDC1 CD40 function in the TDLN as critical for effective antitumor TRM development. Citation Format: Michihisa Kono, Shin Saito, Geoff Ivison, Ayano Kondo, Aaron Mayer, Jonathan D. Schoenfeld, Ann Marie Egloff, Ravindra Uppaluri. Tissue-resident memory CD8+ T cells correlate with anti-PD-1 response in head and neck cancer and expand upon cDC1 activation in tumor-draining lymph nodes to overcome PD-1 resistance [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-078.
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».