T-cell responses against CD19(+) pediatric acute lymphoblastic leukemia mediated by bispecific T-cell engager (BiTE) are regulated contrarily by PD-L1 and CD80/CD86 on leukemic blasts Journal Article


Authors: Feucht, J.; Kayser, S.; Gorodezki, D.; Hamieh, M.; Döring, M.; Blaeschke, F.; Schlegel, P.; Bösmüller, H.; Quintanilla-Fend, L.; Ebinger, M.; Lang, P.; Handgretinger, R.; Feuchtinger, T.
Article Title: T-cell responses against CD19(+) pediatric acute lymphoblastic leukemia mediated by bispecific T-cell engager (BiTE) are regulated contrarily by PD-L1 and CD80/CD86 on leukemic blasts
Abstract: T-cell immunotherapies are promising options in relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We investigated the effect of co-signaling molecules on T-cell attack against leukemia mediated by CD19/CD3-bispecific T-cell engager. Primary CD19+ ALL blasts (n≥10) and physiologic CD19+CD10+ bone marrow precursors were screened for 20 co-signaling molecules. PD-L1, PD-1, LAG-3, CD40, CD86, CD27, CD70 and HVEM revealed different stimulatory and inhibitory profiles of pediatric ALL compared to physiologic cells, with PD-L1 and CD86 as most prominent inhibitory and stimulatory markers. PD-L1 was increased in relapsed ALL patients (n=11) and in ALLs refractory to Blinatumomab (n=5). Exhaustion markers (PD-1, TIM-3) were significantly higher on patients' T cells compared to physiologic controls. T-cell proliferation and effector function was target-cell dependent and correlated to expression of co-signaling molecules. Blockade of inhibitory PD-1-PD-L and CTLA- 4-CD80/86 pathways enhanced T-cell function whereas blockade of co-stimulatory CD28-CD80/86 interaction significantly reduced T-cell function. Combination of Blinatumomab and anti-PD-1 antibody was feasible and induced an anti-leukemic in vivo response in a 12-year-old patient with refractory ALL. In conclusion, ALL cells actively regulate T-cell function by expression of co-signaling molecules and modify efficacy of therapeutic T-cell attack against ALL. Inhibitory interactions of leukemiainduced checkpoint molecules can guide future T-cell therapies.
Keywords: t cells; pd-l1; blinatumomab; immune checkpoints; cd80/86; pediatric acute lymphoblastic leukemia
Journal Title: Oncotarget
Volume: 7
Issue: 47
ISSN: 1949-2553
Publisher: Impact Journals  
Date Published: 2016-11-22
Start Page: 76902
End Page: 76919
Language: English
DOI: 10.18632/oncotarget.12357
PROVIDER: scopus
PUBMED: 27708227
PMCID: PMC5363558
DOI/URL:
Notes: Article -- Export Date: 3 January 2017 -- Source: Scopus
Altmetric
Citation Impact
MSK Authors
  1. Mohamad   Hamieh
    18 Hamieh
  2. Judith Carolin Feucht
    15 Feucht