CD33 $ BiTE^{®} $ molecule-mediated immune synapse formation and subsequent T-cell activation is determined by the expression profile of activating and inhibitory checkpoint molecules on AML cells

Abstract Bispecific T-cell engager ($ BiTE^{®} $) molecules recruit T cells to cancer cells through CD3ε binding, independently of T-cell receptor (TCR) specificity. Whereas physiological T-cell activation is dependent on signal 1 (TCR engagement) and signal 2 (co-stimulation), BiTE molecule-mediated T-cell activation occurs without additional co-stimulation. As co-stimulatory and inhibitory molecules modulate the strength and nature of T-cell responses, we studied the impact of the expression profile of those molecules on target cells for BiTE molecule-mediated T-cell activation in the context of acute myeloid leukemia (AML). Accordingly, we created a novel in vitro model system using murine Ba/F3 cells transduced with human CD33 ± CD86 ± PD-L1. T-cell fitness was assessed by T-cell function assays in co-cultures and immune synapse formation by applying a CD33 BiTE molecule (AMG 330). Using our cell-based model platform, we found that the expression of positive co-stimulatory molecules on target cells markedly enhanced BiTE molecule-mediated T-cell activation. The initiation and stability of the immune synapse between T cells and target cells were significantly increased through the expression of CD86 on target cells. By contrast, the co-inhibitory molecule PD-L1 impaired the stability of BiTE molecule-induced immune synapses and subsequent T-cell responses. We validated our findings in primary T-cell-AML co-cultures, demonstrating a PD-L1-mediated reduction in redirected T-cell activation. The addition of the immunomodulatory drug (IMiD) lenalidomide to co-cultures led to stabilization of immune synapses and improved subsequent T-cell responses. We conclude that target cells modulate CD33 BiTE molecule-dependent T-cell activation and hence, combinatorial strategies might contribute to enhanced efficacy..

Medienart:

E-Artikel

Erscheinungsjahr:

2023

Erschienen:

2023

Enthalten in:

Zur Gesamtaufnahme - volume:72

Enthalten in:

Cancer immunology immunotherapy - 72(2023), 7 vom: 11. Apr., Seite 2499-2512

Sprache:

Englisch

Beteiligte Personen:

Marcinek, Anetta [VerfasserIn]
Brauchle, Bettina [VerfasserIn]
Rohrbacher, Lisa [VerfasserIn]
Hänel, Gerulf [VerfasserIn]
Philipp, Nora [VerfasserIn]
Märkl, Florian [VerfasserIn]
Strzalkowski, Thaddäus [VerfasserIn]
Lacher, Sonja M. [VerfasserIn]
Udiljak, Dragica [VerfasserIn]
Spiekermann, Karsten [VerfasserIn]
Theurich, Sebastian [VerfasserIn]
Kobold, Sebastian [VerfasserIn]
Kischel, Roman [VerfasserIn]
James, John R. [VerfasserIn]
Bücklein, Veit L. [VerfasserIn]
Subklewe, Marion [VerfasserIn]

Links:

Volltext [kostenfrei]

BKL:

44.81$jOnkologie

44.45$jImmunologie

Themen:

Acute myeloid leukemia
Bispecific antibodies
Checkpoint molecule (PD-L1)
Costimulation (CD86)
Immune synapse

RVK:

RVK Klassifikation

Anmerkungen:

© The Author(s) 2023

doi:

10.1007/s00262-023-03439-x

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

OLC2143839154

Zugang & Verfügbarkeit




Zugehörige Publikationen/Bände

    Haven't found what you're looking for?