Expression of Programmed Death 1 Ligand in Different Compartments of Chronic Lymphocytic Leukemia

Abstract

Background: The programmed death 1 (PD-1) receptor pathway is responsible for the negative regulation of both T and B lymphocytes upon activation of these cells. There is growing evidence that chronic lymphocytic leukemia (CLL) cells exploit the PD-1 ligand (PD-L1) to resist antitumor immune reactions and maintain their survival by shaping their own microenvironment. Methods: We used a quantitative RT-PCR method to analyze PD-L1 gene expression in bone marrow and peripheral blood mononuclear cells, representing the proliferation and accumulation compartments of CLL. Results: PD-L1 expression was found to be significantly higher in 112 CLL patients than in controls. Levels of PD-L1 expression in bone marrow and peripheral blood were comparable and showed a positive correlation. Furthermore, expression of PD-L1 strongly correlated with expression of PD-1 receptor in mononuclear cells from the same compartment, and was not affected by incubation with immunomodulatory drug thalidomide. Conclusion: PD-L1 expression is shared between CLL cells localized in distinct disease compartments, demonstrating that PD-1/PD-L1 a universal target for therapy.

Coevolution of Leukemia and Host Immune Cells in Chronic Lymphocytic Leukemia

“…Higher levels of CTLA-4 and PD-1 have been consistently associated with rapidly progressive disease and worse outcome, supporting the notion of T cell exhaustion as an immune escape mechanism during CLL progression (Motta et al 2005; Ramsay et al 2008; Nunes et al 2012; Brusa et al 2013), even while the association between these features and clinical stage have not been strong (Gassner et al 2012; Brusa et al 2013; Grzywnowicz et al 2015; Rusak et al 2015; Novák et al 2015). Recently, antibodies targeting the PD-1/PD-L1 interaction have demonstrated impressive antitumor activity in solid and hematologic malignancies, highlighting the therapeutic opportunity for targeting the modulation of T cell inhibitory molecules (Topalian et al 2012; Armand et al 2013; Ansell et al 2015).…”

Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL

“…30 All patients who received $1 dose were included for analysis. Patients were evaluated at screening and at months 3, 6, and 12 for efficacy by computed tomography or 18 F-fluorodeoxyglucose-positron emission tomography (PET), or as needed for clinical assessment. Bone marrow (BM) examination was performed at months 6 and 12, or as needed for clinical assessment for response.…”

“…[14][15][16][17][18] Exhausted effector or effector memory T cells in CLL patients overexpress PD-1 and are defective to form immune synapse with leukemic B cells. [19][20][21] Incubation of PD-1-blocking antibody with CLL T cells restores the normal immune synapse between peripheral T cells and CLL leukemic cells.…”

The emerging role of immune checkpoint inhibition in malignant lymphoma

“…T cells isolated from CLL patients have higher expression of checkpoint molecules such as CTLA-4 and PD-1. 60,61 The cells' cytotoxic and proliferating capacities are reduced, but they maintain the ability to produce cytokines. 62 Unlike the situation in most hematologic malignancies, PD-1 is expressed on both T and CLL cells, while PD-L1 is also highly expressed in the different compartments of the tumor microenvironment, including CLL cells.…”

“…62 Unlike the situation in most hematologic malignancies, PD-1 is expressed on both T and CLL cells, while PD-L1 is also highly expressed in the different compartments of the tumor microenvironment, including CLL cells. 61,63 Preclinical data on anti-PD-1 effects in CLL demonstrated restored CD8 T-cell cytotoxicity, immune synapse formation and prevention of CLL development in TCL-1 mouse models. 64,65 These observations and other preclinical data suggesting the importance of additional immune checkpoint pathways 66 provide a strong rationale for investigating immunomodulating therapies in CLL.…”