Abstract 1154: Investigating the functional role of GPNMB in glioblastoma and the tumor immune microenvironment and its targeted elimination using CAR-Ts
Notice bibliographique
Résumé
Abstract Glycoprotein nonmetastatic melanoma protein B (GPNMB) is known to be active in the extracellular matrix of glioblastoma and has been identified as a promising immunotherapy target for both tumor cells and immunosuppressive macrophages. Methods: Immunohistochemistry was performed on patient derived xenograft (PDX) brains and tissue samples of 16 patient matched primary/recurrent GBMs as well as 23 normal organ tissues. Whole cell proteomics was performed on 43 matched primary/recurrent GBM samples. Flow cytometry measured surface expression levels of GPNMB to confirm CAR-T accessibility. CRISPR/Cas9 was used to eliminate expression in GBM lines to measure proliferation and mouse survival times. GPNMB knockout clones were generated in GL261 and engrafted in immunocompetent mice to examine single cell transcriptomes using sciRNAseq at endpoint. A second-generation CAR-T was developed to target GPNMB-expressing populations, and efficacy was interrogated using standard in vitro assays and GBM PDX models. Results: The absence of GPNMB throughout most normal tissues validates the rationale of administering CAR-Ts as a safe modality for patients. GPNMB detected in residual tumors of PDX models treated orthotopically with CD133 CAR-Ts revealed it as a targetable subpopulation of GBM cells and a rational co-target alongside CD133 in the heterogeneous tumor. Tissue microarrays and whole cell proteomics found GPNMB to be upregulated in recurrent GBMs compared to primary (p=0.0349 and p=0.0033 respectively) while being absent in normal tissues. Single cell sequencing data of patient GBMs revealed GPNMB was also highly expressed in tumor-associated macrophages. Eliminating GPNMB in GBM cell lines decreased proliferation (P<0.001) and prolonged survival times in all mouse models (P<0.01) indicating its functional relevance. GPNMB knockout clones displayed downregulation of hallmark signalling pathways of GBM such as PDGFR, TGF-beta, Integrins and Stats, as well as decreased innate/adaptive immune activation. CAR-T cytotoxicity and activation was observed in vitro and in vivo resulting in decreased tumor burden (P<0.001) and increased survival times (P<0.001). Ultimately a CD133+ population was observed in residual tumors of GPNMB CAR-T treated mice at endpoint and surface expression of CD133 and GPNMB revealed co-expression and distinct populations. Conclusions: We show GPNMB influences tumor-intrinsic biology of GBM and is also active in macrophages in the recurrent GBM immune microenvironment. By targeting GPNMB along with CD133, combinatorial therapeutic regimens could target both the cancer stem cell hierarchy and its supportive niche. Administration of both CAR-T cell therapies to humanized mice engrafted with patient-derived GBMs will provide better cytotoxic coverage and potentially provide more durable therapeutic efficacy for GBM patients. Citation Format: Neil Savage, Franz J. Zemp, Nick Mikolajewicz, Hong Han, Chitra Venugopal, Chirayu Chokshi, Nazanin Tatari, Thomas Kislinger, Jason Moffat, Doug Mahoney, Sheila K. Singh. Investigating the functional role of GPNMB in glioblastoma and the tumor immune microenvironment and its targeted elimination using CAR-Ts [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 1154.
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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».