Acute Myeloid Leukemia Stem Cells Escape Innate Immune Surveillance by Macrophages through Interaction with SIRPα
Notice bibliographique
Résumé
Abstract Abstract 499 Introduction: Using a genome-wide positional cloning approach, we previously identified NOD-derived Sirpα as the gene required for support of normal human hematopoiesis in NOD.SCID xenotransplantation assays. NOD.SCID mice bearing other polymorphic Sirpα alleles (e.g. NOD.NOR-Idd13.SCID) do not support human engraftment due to lack of interaction between CD47 expressed on human hematopoietic cells and SIRPα expressed on host macrophages. CD47-SIRPα interaction is also critical for engraftment of human acute myeloid leukemia stem cells (AML-SC): homing, engraftment and migration are all significantly impaired in NOD.NOR-Idd13.SCID compared to NOD.SCID mice. However, AML-SC from different patients are heterogeneous in their ability to engraft NOD.NOR-Idd13.SCID mice, suggesting variable ability to evade innate immune surveillance. We undertook investigations of the mechanisms underlying the decreased engraftment ability of AML-SC in NOD.NOR-Idd13.SCID mice, a better understanding of which will aid in optimizing potential therapeutic approaches aimed at disrupting CD47-SIRPα signaling in AML. Result: To investigate the cellular components of innate immunity that impair AML-SC function, we depleted macrophages in NOD.NOR-Idd13.SCID mice by treatment with clodronate liposomes. Following intravenous injection, homing of AML cells (n=2 patient samples) to bone marrow (BM) and spleen of NOD.NOR-Idd13.SCID mice was not detectable in control mice but was increased in clodronate-treated mice to levels similar to those seen in clodronate-treated NOD.SCID mice. Thus, impaired homing resulting from lack of interaction between CD47 on AML cells and SIRPα on macrophages is rescued by macrophage depletion. To examine the role of macrophages in engraftment and migration of AML-SC, we transplanted NOD.NOR-Idd13.SCID mice intrafemorally with primary AML cells (n=3 patient samples) and treated them weekly with clodronate for 8 weeks. In previous experiments, these AML samples were unable to engraft NOD.NOR-Idd13.SCID mice, or could only engraft the injected femur without migration to other hematopoietic sites. In contrast, clodronate-mediated macrophage depletion in these mice allowed substantial leukemic engraftment by all samples not only in the injected femur, but also in non-injected bones, the spleen and peripheral blood. Thus, evasion of innate immune surveillance by macrophages through interactions between CD47 on AML cells and SIRPα on macrophages is critical for engraftment of AML-SC. To investigate the mechanism of macrophage-mediated impairment of AML-SC function in NOD.NOR-Idd13.SCID mice, we established an in vitro phagocytosis assay using BM-derived macrophages from NOD.SCID and NOD.NOR-Idd13.SCID mice. NOD.NOR-Idd13.SCID macrophages prestimulated with interferon-γ and lipopolysaccharide consistently showed higher levels of phagocytosis of human AML cells in vitro compared to NOD.SCID macrophages. This finding suggests that macrophages eliminate AML cells in vivo through phagocytosis, a process that is inhibited by CD47-SIRPα signaling. The critical importance of CD47-SIRPα signaling for AML-SC function led us to develop a novel human SIRPα (hSIRPα)-Fc fusion protein antagonist for therapy of AML. In pilot studies, in vitro pretreatment of AML cells efficiently blocked homing, engraftment and dissemination following xenotransplantation into NOD.SCID mice. More importantly, in vivo hSIRPα-Fc treatment of NOD.SCID mice repopulated with human AML resulted in dramatic decrease of the leukemic burden in all hematopoietic tissues. Conclusion: Our data show that the interaction between CD47 on AML-SC and SIRPα expressed on host macrophages is critical for the leukemic clone to evade macrophage-mediated innate immune attack. Disruption of this signaling axis, as with hSIRPα-Fc fusion proteins, is an effective therapeutic approach for eradication of AML-SC. Disclosures: Theocharides: Trillium Therapeutics Inc. (TTI): Patents & Royalties, Research Funding. Jin: Trillium Therapeutics Inc. (TTI): Patents & Royalties, Research Funding. Dick: Trillium Therapeutics Inc. (TTI): Patents & Royalties, Research Funding. Danska: Trillium Therapeutics Inc. (TTI): Patents & Royalties, Research Funding. Wang: Trillium Therapeutics Inc. (TTI): Patents & Royalties, Research Funding.
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) | 0,001 | 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 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 ».