Expression, Functions, and Treatment Target of PD-L1 (B7-H1) in Multiple Myeloma

Abstract

Programmed death ligand 1 (PD-L1) expression on myeloma cells is induced by JAK2, STAT3, and MEK1/2-mediated interleukin-6 signaling, a strong inducer of PD-L1 interferon-γ produced by T and natural killer cells, and APRIL produced by osteoclasts in the tumor microenvironment. The soluble form of PD-L1, derived from extracellular domains of PD-L1 molecules expressed in the tumor environment, may also contribute to tumor immune evasion. PD-L1-expressing myeloma cells not only have the ability to escape from the attack of tumor-specific T cells but also high proliferation potential. Furthermore, PD-L1 on myeloma cells delivers a reverse signal to tumor cells through PD-1 binding, resulting in the phosphorylation of Akt accompanied by the acquisition of resistance to anti-myeloma agents. Based on the function of PD-L1 in myeloma, the blockade of the PD-1–PD-L1 pathway is a reasonable treatment in refractory patients. Phase I/II clinical trials of anti-PD-1 antibody combined with immunomodulatory drugs demonstrated excellent effects in heavily pretreated multiple myeloma patients with acceptable tolerability. The timing and combination drug of anti-PD-1/PD-L1 antibodies should be considered to improve clinical effects with low mortality in refractory myeloma patients.