Abstract B022: Tumoral GLI1 controls the resident innate and adaptive tumor immune microenvironment in triple negative breast cancer
Notice bibliographique
Résumé
Abstract Background: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer (BC) cases but due to its aggressive nature and the lack of targeted treatment options, represents a disproportionately higher number of BC-related deaths. Compared to other BC subtypes, TNBCs are more inflamed with M2-like tumor-associated macrophages (TAMs) and cytotoxic T-lymphocytes (CTLs) which are associated with poor and good prognosis, respectively. Clinical trials have proven that immunogenic cancers can be effectively treated through immune checkpoint blockade (ICB), a treatment strategy that prevents cancer cells from silencing CTL-mediated attack. However, CTLs can be suppressed by M2-like TAMs which can limit ICB efficacy and support tumor growth. The hedgehog (HH) signaling pathway is highly activated in TNBC and higher expression of GLI1 is associated with worse overall survival. Recent pan-cancer analyses highlight a significant correlation between activated HH signaling and characteristics of immune evasion. We aim to clarify how activated HH signaling regulates resident innate and adaptive immune cells in the tumor microenvironment (TME) in TNBC. Methods: Primary K14-cre; Brca1 fl/fl ; P53 fl/fl (KBP) murine TNBC cells were transfected with CRISPR/Cas9 + sgRNA targeting GLI1. After isolating single cell clones and confirming GLI1 knockout (KO), KBP and KBP-GLI1-KO cells were orthotopically injected into the mammary fat pad of syngeneic immune-competent female mice and allowed to grow for 6-8 weeks. Tumor volume was measured once tumors were palpable, and tumors were harvested once the largest tumor reached ethical endpoint. Tumors were weighed at harvest and fluorescence activated cell sorting (FACS) was performed to determine if there was an effect on the composition of immune populations. Results: At harvest, KBP-GLI1-KO tumors were delayed in growth and significantly smaller than KBP tumors. FACS analysis showed that GLI1-KO tumors had increased CD4+ and CD8+ T cells and a reduced amount of Foxp3+ CD4+ Tregs. Furthermore, GLI1-KO tumors had significantly fewer F4/80+ CD11b+ TAMs within the TME. Amongst TAM populations, there was reduced CD206+ M2-like TAMs and an increase in CD80+ M1-like TAMs upon loss of GLI1. Similar trends were observed when KBP allografts were treated with the GLI1 inhibitor, GANT61. Immunohistochemical and RNAseq analysis are ongoing. Similar experiments with other KBP-GLI1-KO clones are currently being done. Conclusion: Here, we show that tumoral GLI1 not only promotes tumor growth, but also supports an immunosuppressive TME in TNBC. Abolishing GLI1 converted tumors to a pro-inflammatory phenotype marked by an increase in CD4+ and CD8+ T cells and a reduction in CD206+ M2-like TAMs. Future experiments are aimed at revealing the mechanisms by which GLI1 regulates immune cell recruitment to the TME and testing the effect of combination immunotherapy. Overall, these preliminary findings identify GLI1 as a potential therapeutic target to limit tumor growth and promote anti-tumor immunity. Citation Format: Aidan J Gray, Wanda Marini, Kiichi Murakami, Michael Reedijk. Tumoral GLI1 controls the resident innate and adaptive tumor immune microenvironment in triple negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B022.
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) | 0,003 | 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 ».