Understanding Immune Evasion and Therapeutic Targeting Associated with PD-1/PD-L1 Pathway in Diffuse Large B-cell Lymphoma

Abstract

In tumor microenvironment, the programmed death 1 (PD-1) immune checkpoint has a crucial role of mechanism of T cell exhaustion leading to tumor evasion. Ligands of PD-1, programmed death ligand 1/2 (PD-L1/L2) are over-expressed in tumor cells and participate in prolonged tumor progression and survivals. Recently, clinical trials for patients who failed to obtain an optimal response prior to standardized chemotherapy in several solid cancers have been focused on targeting therapy against PD-1 to reduce disease progression rates and prolonged survivals. Since various inhibitors targeting the immune checkpoint in PD-1/PD-L1 pathway in solid cancers have been introduced, promising approach using anti-PD-1 antibodies were attempted in several types of hematologic malignances. In diffuse large B cell lymphoma (DLBCL) as the most common and aggressive B cell type of non-Hodgkin's lymphoma, anti-PD-1 and anti-PD-L1 antibodies were studies in various clinical trials. In this review, we summarized the results of several studies associated with PD-1/PD-L1 pathway as an immune evasion mechanism and described clinical trials about targeting therapy against PD-1/PD-L1 pathway in DLBCL.

Keywords: PD-1; diffuse large B cell lymphoma; immune checkpoint.

Figure 1

Immune evasion mechanisms associated with the PD-1/PD-L1 signaling pathway in the tumor microenvironment of lymphoma. Upon PD-1 engagement, SHP-1/2 is recruited and then the downstream signal of TCR is inhibited. Ultimately, T-cell exhaustion and tolerance is induced. Meanwhile, PD-L1 expression is promoted via multiple mechanisms, such as alterations of chromosome 9p24.1, MYD88 mutation, SOCS-1 mutation, EBV infection, and increased cytokines (IFN-γ, IL-10); hence cancer-cell proliferation and dissemination is possible.