Abstract B009: Targeting PAR-2 improves tumor antigen presentation and primes the immune system for anti-PD-1 immunotherapy
Notice bibliographique
Résumé
Abstract Identifying mechanisms of resistance to immune checkpoint inhibitors (ICIs) has become a major focus in cancer immunotherapy. Our previous work identified F2RL1 expression in tumors, encoding the G protein-coupled receptor Protease-Activated Receptor-2 (PAR-2), as a negative biomarker for ICI responsiveness. In this study, we evaluated the potential of PAR-2 as a therapeutic target to enhance anti-PD-1 treatment efficacy. Using a sensitive protein-based assay, we observed that systemic PAR-2 activation was significantly elevated across multiple tumor types and correlated with reduced survival of lung cancer patients treated with pembrolizumab and platinum-based chemotherapy. Global PAR-2 deletion in mice significantly increased anti-PD-1 activity and pharmacologic inhibition of PAR-2 using a novel negative allosteric modulator, I-117, significantly potentiated anti-PD-1 therapy in preclinical studies. Mechanistically, PAR-2 inhibition reshaped the tumor microenvironment (TME), notably by reducing the frequency of putative immunosuppressive myeloid cells, as evidenced by flow cytometry using the CD206 marker and by bulk RNA sequencing of MHCII+ CD19- tumor-infiltrating cells, which revealed a downregulation of genes associated with protumorigenic M2-like macrophages. In parallel, PAR-2 inhibition led to a marked enrichment of effector CD8+ T cells within tumors, as well as an increased frequency of CD8+ T cells in tumor-draining lymph nodes (tdLNs), a change not observed with anti–PD-1 monotherapy at the same time point. In contrast, the combination therapy significantly increased the accumulation of central memory CD8+ T cells within the tdLNs, as detected by flow cytometry. These cellular changes were accompanied by a shift in the cytokine milieu, with a trend toward increased Th1-type cytokines and decreased immunosuppressive cytokines, as measured by multiplex ELISA. Finally, using ex vivo co-culture assays with naïve antigen-specific T cells, we demonstrated that PAR-2 inhibition with I-117 significantly enhanced the antigen-presenting capacity of CD11c+ dendritic cells present in tumors and tdLNs. Altogether, these results support a model in which PAR-2 inhibition primes the immune system for optimal tumor antigen presentation, thereby enhancing the effectiveness of PD-1 blockade. Our study provides a compelling rationale for combined use of PAR-2 and PD-1 blockade for cancer immunotherapy. Citation Format: Samya Aouad, Maleck Kadiri, Lucie Giraud, Emma Skora, Thibaut Brugat, Anne-Laure Blayo, Stephan Schann, John Satgg. Targeting PAR-2 improves tumor antigen presentation and primes the immune system for anti-PD-1 immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr B009.
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 | 0,000 |
| 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 | 0,001 | 0,001 |
| 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) | 0,000 | 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 ».