Abstract 2345: SIRPαFc, a CD47-blocking cancer immunotherapeutic, triggers phagocytosis of lymphoma cells by both classically (M1) and alternatively (M2) activated macrophages
Notice bibliographique
Résumé
Abstract Macrophages are characterized by their heterogeneity and plasticity in response to the microenvironment. Although macrophages have the capacity to phagocytose cancer cells that express pro-phagocytic signals, tumor cells often evade macrophage-mediated destruction by increased cell surface expression of CD47, which delivers an anti-phagocytic (“do not eat”) signal by binding the inhibitory signal-regulatory protein α (SIRPα) receptor on the surface of macrophages. We have previously shown that soluble SIRPα-Fc fusion protein (SIRPαFc) neutralizes the suppressive effects of CD47 and promotes macrophage-mediated phagocytosis of tumor cells both in vitro and in vivo. In an attempt to recapitulate the functional and phenotypic heterogeneity of tumor infiltrating macrophages, we have examined the ability of SIRPαFc to trigger phagocytosis of lymphoma cells by six distinctly polarized macrophage populations. We generated human monocyte-derived macrophages (MDMs) and polarized them into M0, M1, M2a, M2b and M2c subsets. These MDMs varied greatly in their expression of myeloid surface markers including CD14, CD11b, CD80, CD86, HLA-DR, CD206, CD200R and CD163; as well as in expression of the Fc gamma receptors (FcγRs) CD16, CD32 and CD64. Next, the ability of SIRPαFc to trigger MDM phagocytosis of lymphoma cells was examined using a flow cytometry-based assay. Blockade of CD47 on the tumor cells using SIRPαFc dramatically increased phagocytosis of tumor cells by all subsets, with M1 and M2c MDMs being superior at phagocytosis. Moreover, we found that M0, M2a and M2b MDMs, which exhibited slightly lower phagocytic capabilities, were remarkably plastic in nature and could readily be re-polarized into highly phagocytic MDMs using a variety of agents. This suggests that SIRPαFc will be efficacious in triggering the destruction of cancer cells by the diverse population of MDMs found in vivo. To further understand what drives the phagocytic capacity of polarized MDMs, we analyzed FcγR expression and observed a positive correlation between MDM expression of the high-affinity FcγRI (CD64) and phagocytic activity following SIRPαFc treatment. Moreover, re-polarization of M0, M2a and M2b MDMs resulted in upregulation of FcγRs and enhanced tumor cell phagocytosis. Finally, by individually blocking CD16, CD32 and CD64 on MDMs prior to the phagocytosis assay, we found that the low-affinity FcγRs CD16 and CD32 also contribute to SIRPαFc-mediated phagocytosis of lymphoma cells. In conclusion, SIRPαFc triggered phagocytosis of lymphoma cells by a diverse panel of polarized MDMs, which required MDM expression of FcγRs. These data support the evaluation of SIRPαFc in cancer patients and a clinical study of SIRPαFc in patients with lymphoma and other hematological malignancies is currently in progress. Citation Format: Gloria H. Y. Lin, Vien Chai, Vivian Lee, Karen Dodge, Tran Truong, Mark Wong, Lisa D. S. Johnson, Xinli Pang, Penka S. Petrova, Robert A. Uger, Natasja N. Viller. SIRPαFc, a CD47-blocking cancer immunotherapeutic, triggers phagocytosis of lymphoma cells by both classically (M1) and alternatively (M2) activated macrophages. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2345.
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 ».