Abstract B007: Tissue-Specific B Cell Differentiation Limits Anti-Tumor Efficacy of Radiation and Immunotherapy
Notice bibliographique
Résumé
Abstract Despite recent advances in triple-negative breast cancer (TNBC) biology and new therapies, this aggressive subtype remains difficult to treat. A key obstacle is the immunosuppressive tumor microenvironment (TME), often dominated by myeloid cells that impair anti-tumor immunity. Radiation therapy (RT), used as an in-situ vaccine, enhances tumor immunogenicity and has shown promise when combined with immune checkpoint blockade (ICB) in preclinical and clinical settings1-3. We previously found that combining RT with CTLA-4 blockade and a CD40 agonist antibody (CD40a), which activates myeloid cells, led to profound tumor regression and occasional complete responses in a rapidly metastasizing TNBC mouse model4. However, CD40a did not improve control of lung metastases beyond that achieved with RT and CTLA-4 blockade. In tumors, CD40a induced remodeling of dendritic cell and macrophage populations, along with enrichment in B cell–associated gene signatures. As CD40 signaling can promote either effector or regulatory B cell responses depending on context5, we hypothesized that triple therapy induces organ-specific B cell differentiation that may hinder systemic immune control. We first assessed systemic versus local effects of CD40a on B cells in naïve and tumor-bearing (4T1) mice. In both settings, CD40a expanded splenic B cells and increased MHC-II+ expression. In lungs, tumor implantation alone led to increased B cell infiltration, even without CD40a. However, these lung B cells showed reduced activation in untreated tumor-bearing mice, only partially restored by CD40a, suggesting a distinct, potentially immunosuppressive phenotype. To evaluate this in the context of RT + CTLA-4 blockade + CD40a, we analyzed B cells from lungs and tumors via multiparametric flow cytometry and observed that CD40a consistently shifted B cell profiles across compartments. Among B cells, we identified regulatory B cells (Breg) as expressing TIM1, CD138, CD5, CD39, and FasL. CD40a decreased Breg infiltration in tumors but significantly increased it in lungs. In both tissues, Breg marker expression correlated with tumor or lung burden. Given TIM1’s role in IL-10–producing Bregs—and its capacity to suppress T cells independently of IL-10—6-8 we tested a TIM1-blocking antibody in combination with RT + CTLA-4 blockade + CD40a. While TIM1 blockade did not enhance tumor control, it markedly reduced lung Bregs. Our data highlight organ-specific B cell responses following CD40a-based immunotherapy and suggest that lung-resident Bregs may limit systemic immune efficacy. Ongoing work focuses on defining mechanisms of Breg-mediated suppression and, in collaboration with bioengineers, on developing intra-tumoral delivery strategies to reduce systemic immunosuppressive effects of agents like CD40a. 1-PMID: 29180535 2-PMID: 33476307 3-PMID: 30397353 4-PMID: 37620372 5-PMID: 19265127 6-PMID: 25582854 7-PMID: 31511630 8-PMID: 31685302 Citation Format: Maud Charpentier, David Sprott, Sandra Demaria. Tissue-Specific B Cell Differentiation Limits Anti-Tumor Efficacy of Radiation and 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 B007.
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) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 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) | 0,001 | 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 ».