Abstract A023: Myeloid checkpoint blockade potentiates radiotherapy by modulating dendritic cells and reducing Treg-driven immunosuppression
Notice bibliographique
Résumé
Abstract Fractionated focal radiation therapy (RT) induces immunogenic cell death and activates the type I interferon pathway via the cGAS/STING pathway, promoting tumor antigen cross-presentation by conventional dendritic cells (cDCs) and driving tumor-specific T-cell activation. However, the impact of RT on tumor regression is often limited by its complex effects on the tumor immune microenvironment (TiME). Several studies have shown that RT increases both the frequency and functional activity of regulatory T cells (Tregs), due in part to their intrinsic radioresistance and to RT-induced modulation of recruitment signals such as TGFβ, CCL17, and CCL221-2. In a recent study, we showed that RT combined with immunotherapy can remodel the TiME3, et persistent infiltration of activated Tregs can dampen the full immunostimulatory effects of RT-driven viral mimicry responses4. Here, we evaluated whether combining RT with blockade of the myeloid checkpoint SIRPα could modulate Treg infiltration and activity. Using mouse models of luminal (TSA) and triple-negative (AT3) breast cancer, we tested RT in combination with a blocking anti-SIRPα antibody (MY1; SIRPα-b). While MY1 monotherapy showed minimal activity, its combination with RT led to enhanced regression of irradiated tumors and inhibition of non-irradiated (abscopal) tumor growth in both tumor models. This effect was lost upon conditional cDC depletion using Zbtb46-DTR mice, highlighting the importance of cDCs in mediating the therapeutic synergy. To dissect the immune mechanisms underlying this synergy, we performed single-cell RNA-sequencing and CITE-seq on CD45+ tumor-infiltrating cells from TSA tumors treated with RT ± SIRPα-b. We observed a significant reduction in Treg infiltration in SIRPα-b–treated tumors, with or without RT. Furthermore, expression of Treg activation markers OX40, CTLA-4, and GITR was reduced, particularly in the RT + SIRPα-b group. Among infiltrating CD45+ cells, expression of Treg recruiting Ccl22 and Ccl17 chemokines was observed only in a highly activated cluster of CCR7high cDCs expressing SIRPα, CXCL16, PD-L1, and IL-15Rα. Notably, expression of both chemokines was strongly decreased following SIRPα-b treatment, suggesting that SIRPα signaling supports Treg recruitment via this cDC population.Studies to understand the mechanisms of Treg recruitment to the tumor via chemokine secretion by CCR7high cDCs and their role in tumor regression after RT + SIRPα-b are underway. Intra-tumoral CCR7high cDCs are known to support the activation and cytotoxic function of CD8+ T cells and NK cells in the tumor through transpresentation of Il-155. Our results suggest that this population also plays a key immunoregulatory role in shaping the TiME. Targeting the CD47/SIRPα axis may thus improve RT efficacy by modulating the dual functions of CCR7high cDCs in both effector stimulation and Treg recruitment. 1- PMID: 28970196 2- PMID: 30042205 3- PMID: 37620372 4- doi: 10.1038/s41392-023-01462-z 5- PMID: 34343496 Citation Format: Maud Charpentier, Claire Lhuillier, Alicia Alonso, Doron Betel, Paul Zumbo, Maider Astorkia Amiama, Sergio Trombetta, Sandra Demaria. Myeloid checkpoint blockade potentiates radiotherapy by modulating dendritic cells and reducing Treg-driven immunosuppression [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 A023.
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 | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,002 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».