Abstract 3651: The role of caspase-1 in basal-like breast cancer and the tumor microenvironment
Notice bibliographique
Résumé
Abstract Introduction: Breast cancer is the most common malignancy in women world-wide. Basal-like breast cancer (BLBC) is an aggressive subtype with poor prognosis for which there are no known targeted therapies. Understanding what drives complex cell-cell interactions within the tumor microenvironment (TME) is critical to developing new strategies. BLBC has previously been shown to have high expression of the inflammatory cytokine IL1β, which then promotes the recruitment of pro-tumoral tumor-associated macrophages (TAMs) to the TME. Here we report that BLBC is uniquely capable of IL1β secretion due to elevated expression of caspase-1, a key component of the inflammasome required for IL1β maturation. Methods: Using publicly available gene expression data sets, the association between caspase-1, breast cancer subtype and estrogen receptor (ER) co-expression was examined. These associations were further assessed in vitro by exposing luminal (T47D/MCF7) or BLBC (MDA-MB231) cell lines to siER knockdown or ER overexpression. Using both a CRISPR/Cas9 generated caspase-1 knockout (KO) BLBC mouse line as well as pharmacological inhibition with the caspase-1 inhibitor VX-765, the effect of caspase-1 on tumor growth was studied in syngeneic immunocompetent mice. Immune infiltrates were assessed via flow cytometry of the excised murine tumors as well as immunohistochemistry. To prove these results were IL1β specific, caspase-1 KO tumor allografts containing self-cleaving IL1β were used for comparison. Finally, to determine potential synergy between caspase-1 and immune checkpoint inhibition, wild type and caspase-1 KO allografts were simultaneously treated with anti-PD1 immunotherapy. Tumor growth and immune infiltrates were analyzed between the treatment groups as stated above. Results: Caspase-1 was found to be associated with the basal-like subtype and have an inverse relationship with ER expression. In vitro, inhibition of ER increased caspase-1 expression, whereas ER overexpression decreased caspase-1. Caspase-1 KO or pharmacological inhibition resulted in a significant decrease in tumor growth and TAM infiltration, and these findings were rescued back to wild type levels with the addition of a self-cleaving IL1β. Finally, caspase-1 inhibition reversed resistance to anti-PD1 immunotherapy in murine allografts, resulting in significant deceleration of tumor growth when used in combination. Summary: The lack of ER in BLBC promotes caspase-1 expression, allowing IL1β maturation, macrophage recruitment and tumor progression. Genetic or pharmacologic inhibition of caspase-1 inhibits TAM recruitment and reverses resistance to immune checkpoint inhibition in BLBC. Conclusions: Our data provides new insights into the biology of BLBC and identifies the combination of caspase-1/IL1β inhibition and immunotherapy as a novel therapeutic strategy to combat this disease. Citation Format: Wanda Marini, Weiyue Zheng, Kiichi Murakami, Pamela S. Ohashi, Michael Reedijk. The role of caspase-1 in basal-like breast cancer and the tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3651.
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 | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,002 | 0,001 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,002 |
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 ».