Soluble PD-1 Ligands May Contribute to the Pathogenesis of Waldenström Macroglobulinemia

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New evidence appears to support the potential utility of checkpoint inhibitors in Waldenström macroglobulinemia.
New evidence appears to support the potential utility of checkpoint inhibitors in Waldenström macroglobulinemia.

Soluble PD-1 ligand levels were found to be high in patients with Waldenström macroglobulinemia (WM), suggesting the soluble ligands have a potential role in disease progression, according to the authors of a study published in Blood Advances.1

Cytokines in the bone marrow and plasma in WM can modulate the expression of immune checkpoint molecules, the investigators confirmed. Increases in soluble checkpoint molecules were also found to reduce T-cell proliferation; this T-cell inhibition contributes to disease progression.

Researchers from the Mayo Clinic in Rochester, Minnesota, examined 28 samples from patients with WM and compared them with controls from 20 bone marrow samples from patients who had undergone hip-replacement surgery. The investigators also conducted tests on WM cell lines.

Compared with normal bone marrow, the bone marrow in patients with WM demonstrated a significantly elevated level of gene expression of PD-L1 (= .003 for CD19/138cells; = .03 for CD19+/138+cells) — but no difference was found between the samples regarding PD-1 expression. Levels of soluble PD-L1 and PD-L2 in both the bone marrow and peripheral blood serum of patients with WM were found to be elevated, “indicating that WM BM cells secrete the ligands into the tumor microenvironment.”

Despite seeing increased levels of cytokine-mediated gene expression of PD-L1 or PD-L2 in WM, the researchers noted that this had little impact on the expression of ligands on the surface of cells. The implication of such a finding is that not only membrane-bound ligands in bone marrow, but also soluble PD-1 ligands, can influence T-cell function.

“Based on the data presented in this study, therapeutic intervention using PD-L1 inhibitors, together with the agents that target malignant cells, could benefit patients with WM,” the authors concluded.

The presence or absence of a mutated MYD88 gene, a common genomic aberration in WM, did not influence the findings across disease groups — although both of these groups demonstrated higher levels of immune checkpoint molecules compared with normal bone marrow controls.

Reference

  1. Jalali S, Price-Troska T, Paludo J, et al. Soluble PD-1 ligands regulate T-cell function in Waldenstrom macroglobulinemiaBlood Adv. 2018;2(15):1985-1997.

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