CD200 and PD1-L1 in AML Are Associated with Expanded PD-1+ Late Differentiated CD8+ T Cells and a Decreased CD4:CD8 Ratio: a New Link Between Distinct Immunosuppressive Pathways

Long-term remission for acute myeloid leukemia (AML) is still not achieved for the majority of patients and consequently there is a need for new treatments to consolidate current therapy. A promising approach is to augment the anti-tumor immune response in these patients; however most cancers do not activate immune effector cells because they express immunosuppressive ligands. Previously we showed that CD200 overexpression on AML blasts suppresses memory CD4+ and CD8+ T cell effector function through engagement with CD200 receptor (CD200R) on these cells. Blocking CD200:CD200R, however, only partially restored T cell activity, suggesting that alternative immunosuppressive mechanisms were involved. Recently, promising clinical outcomes have been reported for melanoma and non-small cell lung cancer using humanized antibodies targeting another immunosuppressive receptor, PD-1, and we therefore investigated whether this could be contributing to the immunosuppression of T cell effector responses in CD200hi AML patients. Initially, we investigated whether CD200 and the immunosuppressive ligand for PD-1, PD1-L1, were co-expressed in AML blasts at diagnosis. Affymetrix gene expression data from 158 AML blasts showed that AML patients in the upper quartile for CD200 expression (CD200hi) had 10-fold higher levels of PD1-L1 expression compared to CD200lo (lower quartile) patients. Analysis of CD200 and PD1-L1 protein expression on AML blast cells confirmed this association at the protein level (r2 = 0.49; p50%) reduction in the frequency of activated 7E7 T cells; however, when both CD200 and PD1-L1 were co-expressed, T cell activation was almost ablated (~90% reduction; p<0.01). Moreover, the strength of the TNFα response was also reduced in co-culture assays where either CD200 or PD1-L1 were present, indicating a direct effect at the level of CD8+ T cell function (2.8 ± 0.5 vs 1.7 ± 0.5; p