957 Modulation of the tumor immune microenvironment by low dose antibody-based radiopharmaceutical therapy (RPT) and direct visualization of RPT analog microdistribution by imaging mass cytometry
Notice bibliographique
Résumé
Background Radiopharmaceutical therapy (RPT) can directly kill tumors or, at lower doses, modulate the tumor microenvironment (TME). The range of beta particles (millimeters) produces a field effect; however, alpha-particle range is limited to a few cell diameters. Thus, an understanding of the spatial distribution of radionuclides at the cellular level is critical for development of RPT but remains challenging. Imaging Mass Cytometry™ (IMC™) technology could provide a direct route for visualization of RPT deposition and concurrent profiling of the TME.Prostate stem cell antigen (PSCA), overexpressed in pancreatic cancers, can be targeted using an engineered antibody fragment (A2DM) labeled with beta- or alpha-emitting radionuclides (177Lu or 225Ac). These RPT agents inhibited growth of pancreatic KPC-hPSCA (human PSCA) tumors in a syngeneic hPSCA knock-in mouse. Attempts to detect the stable decay product of 177Lu (177Hf), were unsuccessful since therapeutic radionuclides are administered at trace levels.Here, A2DM was labeled at mass levels with 169Tm to provide a cold RPT analog to enable detection and localization by IMC. In parallel, spatial profiling of changes to the TME following low-dose of alpha- or beta-RPT was assessed by multiplex IMC at the tissue and cellular level.Methods A2DM was conjugated to 169Tm-DOTA to generate the cold RPT analog. KPC-hPSCA tumor-bearing mice received escalating protein doses of 169Tm-A2DM (10-100µg), and tumors harvested at 48 hr. For low-dose RPT, mice were administered 225Ac-A2DM or 177Lu-A2DM, and tumors collected at days 4, 7 and/or 14. Tissues were formalin-fixed and processed for IMC staining with a 33-marker panel.Results The 169Tm-labeled analog was visualized in tumor sections by IMC in a protein dose-dependent manner (figure 1). IMC confirmed high hPSCA expression across most tumors, with some heterogeneity. KPC-hPSCA tumors exhibited dense stroma and an immunosuppressive TME enriched in myeloid-derived suppressor cells (MDSCs: CD11b+ Ly6G+ Arginase+ iNOS+) and tumor-associated macrophages (TAMs: F4/80+ CD206+). RPT-treated tumors showed a reduction in MDSCs, suggesting alleviation of immunosuppression, particularly at day 7 following 225Ac-RPT and day 4 following 177Lu-RPT (figure 2).Conclusions IMC technology was successfully employed to visualize the spatial distribution of an RPT analog and to assess RPT-induced changes in the TME. A reduction in immunosuppressive cells was observed following low-dose alpha- or beta-RPT. Going forward, co-administration of RPT agents labeled with mass amounts of cold radiometal and trace therapeutic radionuclide should enable evaluation of the RPT microdistribution and concurrent spatial evaluation of radiation effects on the TME, facilitating development of effective RPT strategies.Ethics Approval Animal studies were conducted under a protocol approved by the City of Hope Institutional Animal Care and Use Committee; approval number 18118.Abstract 957 Figure 1Direct visualization of RPT analog. A) 177Lu-A2DM RPT and cold analog 169Tm-A2DM. B) Dose-dependent visualization of 169Tm-A2DM in KPC-hPSCA tumors. C) Co-visualization of 169Tm analog with CD31, hPSCA, and CD45 in tumors using Hyperion XTI tissue modeAbstract 957 Figure 2Reduction in MDSCs in α-RPT- and β-RPT-treated tumors. IMC shows reduced MDSCs (CD11b+ Arginase+) in A) KPC-hPSCA tumors treated with 150nCi/10µg 225Ac-A2DM at day 7 or B) 75µCi/10µg 177Lu-A2DM at day 4 compared to controls. Imaged on Hyperion XTi
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) | 0,004 | 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 ».