Programmed Death Ligand 1 Is Expressed by Non-Hodgkin Lymphomas and Inhibits the Activity of Tumor-Associated T Cells

Purpose: Programmed death ligand 1 (PD-L1) is expressed on antigen-presenting cells and inhibits activation of T cells through its receptor PD-1. PD-L1 is aberrantly expressed on some epithelial malignancies and Hodgkin lymphomas and may prevent effective host antitumor immunity. The role of PD-L1 in non-Hodgkin lymphomas (NHL) is not well characterized. Experimental Design: PD-L1 expression was analyzed in cell lines and lymphoma specimens by using flow cytometry and immunohistochemistry. Functional activity of PD-L1 was studied by incubating irradiated lymphoma cells with allogeneic T cells with or without anti-PD-L1 blocking antibody; T-cell proliferation and IFN-gamma secretion served as measures of T-cell activation. Similar experiments were conducted using cultures of primary lymphoma specimens containing host T cells. Results: PD-L1 was expressed uniformly by anaplastic large cell lymphoma (ALCL) cell lines, but rarely in B-cell NHL, confined to a subset of diffuse large B-cell lymphomas (DLBCL) with activated B-cell features (3 of 28 cell lines and 24% of primary DLBCL). Anti-PD-L1 blocking antibody boosted proliferation and IFN-gamma secretion by allogeneic T cells responding to ALCL and DLBCL cells. In autologous cultures of primary ALCL and DLBCL, PD-L1 blockade enhanced secretion of inflammatory cytokines IFN-gamma, granulocyte macrophage colony-stimulating factor, interleukin (IL)-1, IL-6, IL-8, IL-13, TNF-alpha, and macrophage inflammatory protein-1 alpha. In establishing cell lines from an aggressive PD-L1(+) mature B-cell lymphoma, we also noted that PD-L1 expression could be lost under certain in vitro culture conditions. Conclusions: PD-L1 may thwart effective antitumor immune responses and represents an attractive target for lymphoma immunotherapy. Clin Cancer Res; 17(13); 4232-44. (C) 2011 AACR.