Expression of Immune Checkpoint Receptors on T-Cells and Their Ligands on Leukemia Blasts in Childhood Acute Leukemia

Background: Possible correlations between the expression of immune checkpoint molecules and prognosis in childhood acute leukemia were investigated. Materials and Methods: The expression of programmed-death 1 (PD1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and B-and T-lymphocyte attenuator (BTLA) was determined by flow cytometry on peripheral alpha beta(+) and gamma delta(+) T-cells from patients with newly diagnosed acute lymphoblastic leukemia (ALL) (n= 9) or acute myeloid leukemia (AML) (n= 12), and from healthy volunteers (n= 7). The expression of programmed-death ligand 1 (PD-L1), B7-1, B7-2, human leukocyte antigen-ABC (HLA-ABC), and herpesvirus-entry mediator (HVEM) ligands was determined on leukemia blasts. Results: PD1 expression on alpha beta(+) and gamma delta(+) T-cells was significantly higher in patients with ALL than in those with AML (p= 0.0019 and 0.0239, respectively). CTLA-4 expression was moderately higher on alpha beta(+) and gamma delta(+) T-cells in ALL (p= 0.077 and 0.077, respectively), whereas HLAABC expression was significantly higher in AML blast cells (p= 0.0182). The expression of CTLA-4 on gamma delta(+) T-cells and the B7-2 ligand on blasts was higher in patients with highrisk ALL (p= 0.02 and 0.02, respectively). In AML, PD1 expression on alpha beta(+) T-cells was higher in the intermediaterisk group (p= 0.05), whereas HVEM expression was significantly higher in the low-risk group (p= 0.02). Expression of CTLA-4 on gamma delta(+) T-cells and PD-L1 on blasts were both associated with poor relapse-free survival outcomes in ALL (p= 0.049). Conclusion: The higher expression of immune checkpoint molecules, in particular, CTLA-4 and PD-L1 are associated with a poorer prognosis in ALL, suggesting that selective use of the immune checkpoint blockade might improve the clinical outcomes in patients with ALL.