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:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-84998886281&doi=10.18632%2foncotarget.12357&partnerID=40&md5=03820b85b7a318379236660729cf55e5
Notes:	Article -- Export Date: 3 January 2017 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/102938