Research Papers:

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

Judith Feucht, Simone Kayser, David Gorodezki, Mohamad Hamieh, Michaela Döring, Franziska Blaeschke, Patrick Schlegel, Hans Bösmüller, Leticia Quintanilla-Fend, Martin Ebinger, Peter Lang, Rupert Handgretinger and Tobias Feuchtinger _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:76902-76919. https://doi.org/10.18632/oncotarget.12357

Metrics: PDF 4552 views  |   HTML 5843 views  |   ?  


Judith Feucht1,2, Simone Kayser1, David Gorodezki1, Mohamad Hamieh2, Michaela Döring1,3, Franziska Blaeschke3, Patrick Schlegel1, Hans Bösmüller4, Leticia Quintanilla-Fend4, Martin Ebinger1, Peter Lang1, Rupert Handgretinger1, Tobias Feuchtinger1,3

1Department of General Pediatrics, Hematology and Oncology, Children’s University Hospital Tübingen, Tübingen, Germany

2Memorial Sloan Kettering Cancer Center, Center for Cell Engineering, New York, NY, USA

3Dr. von Hauner Children’s Hospital, Ludwig Maximilians University Munich, Munich, Germany

4Institute of Pathology, University Hospital Tübingen, Tübingen, Germany

Correspondence to:

Tobias Feuchtinger, email: [email protected]

Keywords: pediatric acute lymphoblastic leukemia, T cells, immune checkpoints, PD-L1, CD80/86, blinatumomab

Received: April 18, 2016    Accepted: September 02, 2016    Published: September 30, 2016


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 leukemia-induced checkpoint molecules can guide future T-cell therapies.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 12357