TY - JOUR AU - Davide Brusa, AU - Sara Serra, AU - Marta Coscia, AU - Davide Rossi, AU - Giovanni D’Arena, AU - Luca Laurenti, AU - Ozren Jaksic, AU - Giorgio Fedele, AU - Giorgio Inghirami, AU - Gianluca Gaidano, AU - Fabio Malavasi, AU - Silvia Deaglio, PY - 2013/05/31 Y2 - 2024/03/28 TI - The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia JF - Haematologica JA - haematol VL - 98 IS - 6 SE - Articles DO - 10.3324/haematol.2012.077537 UR - https://haematologica.org/article/view/6698 SP - 953-963 AB - Chronic lymphocytic leukemia is marked by profound defects in T-cell function. Programmed death-1 is a receptor involved in tumor-mediated immunosuppression through binding of the PD-L1 ligand. Multiparametric flow cytometry and immunohistochemistry were used to study PD-1/PD-L1 expression. Functional assays were used to determine the involvement of the PD-1/PD-L1 axis in T-cell responses. PD-1 expression by CD4+ and CD8+ T lymphocytes was significantly higher in 117 chronic lymphocytic leukemia patients than in 33 donors of a comparable age. CD4+ and CD8+ T lymphocytes from chronic lymphocytic leukemia patients displayed increased numbers of effector memory and terminally differentiated cells, respectively, when compared to controls. The number of effector memory CD4+ and terminally differentiated CD8+ lymphocytes positively associated with a more advanced stage of disease, treatment requirements and unfavorable genomic aberrations. Furthermore, leukemic lymphocytes expressed higher levels of PD-L1 than circulating B lymphocytes from normal donors. PD-1 and PD-L1 surface expression spiked in proliferating T and B lymphocytes, suggesting that this interaction works efficiently in activated environments. Within chronic lymphocytic leukemia proliferation centers in the lymph node, CD4+/PD-1+ T lymphocytes were found to be in close contact with PD-L1+ chronic lymphocytic leukemia cells. Lastly, functional experiments using recombinant soluble PD-L1 and blocking antibodies indicated that this axis contributes to the inhibition of IFN-γ production by CD8+ T cells. These observations suggest that pharmacological manipulation of the PD-1/PD-L1 axis may contribute to restoring T-cell functions in the chronic lymphocytic leukemia microenvironment. ER -