University of Worcester Worcester Research and Publications

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

Coles, Steven and Gilmour, M.N. and Reid, R. and Knapper, S. and Burnett, A.K. and Man, S. and Tonks, A. and Darley, R.L. (2014) 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. In: 56th American Society of Hematology Annual Meeting and Exposition, 6th - 9th December 2014, San Francisco. (Unpublished)

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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; p<0.01). The co-expression of CD200 and PD1-L1 on patient AML blast cells, suggested that they cooperated in immunosuppression. In support of this, we found that the CD200 and PD1-L1 cognate co-receptors (CD200R and PD-1 respectively) were present on CD4+ and CD8+ T cells from AML patients. Further characterization of PD-1+ T cells showed that the mean frequency of PD-1+ early differentiated T cells (CD57- CD28+) was increased for CD200hi AML patients CD4+ (19% ± 3 vs 13% ± 3; p<0.05) and CD8+ T cells (21% ± 3 vs 11% ± 2; p<0.05). We also found that the mean frequency of late differentiated CD8+ T cells that have poor anti-tumor function (CD57+ CD28- PD-1+) was almost twice that for CD200hi patients compared with CD200lo (38% ± 6 vs 21% ± 9 respectively; p<0.05). Expansion of these cells was also associated with a decreased CD4:CD8 ratio in these patients (2.1 ± 0.5 vs 3.7 ± 1 for CD200hi and CD200lo respectively; p<0.01). . These findings show for the first time a link between CD200 expression level on AML blast cells and the frequency of PD-1+ late differentiated CD8+ T cells. To directly test whether engagement of CD200 with CD200R was capable of mediating PD-1 up-regulation on CD8+ T cells, we co-cultured a CD8+ CD200R+ T cell clone (7E7) either with K562 cells stably overexpressing CD200 or K562 empty vector controls (negative for CD200). Co-culture with CD200+ cells, significantly increased the frequency of PD-1+ T cells (26% ± 3 vs 17% ± 4; p<0.05) and this was antagonized by CD200 blocking antibody (26% ± 3 vs 21% ± 3; p<0.01). These data show that CD200:CD200R interaction has the capacity to increase the frequency of PD-1+ CD8+ T cells. To model the functional implications of this, we created a series of K562 lines expressing CD200, PD1-L1 or both molecules in combination and analyzed the effect of T cell activation (via TNFα production). We found that both CD200 and PD1-L1 induced a similar (>50%) 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<0.05). These data demonstrate that CD200:CD200R and PD1-L1:PD-1 engagement on T cells can act in tandem to augment immunosuppression of CD8+ T cells. In summary, we show for the first time that the immunosuppressive molecules, CD200 and PD1-L1 appear to be co-regulated on AML blasts and that these can act in combination to profoundly suppress T cell activation. Further, we show that CD200:CD200R engagement induces PD-1+ CD8+ T cells. Taken together we propose a novel CD200/PD1-L1 immunotherapeutic synapse in AML which should be targeted by combining CD200:CD200R and PD1-L1:PD-1 blockade in immunotherapy of AML.

Item Type: Conference or Workshop Item (Poster)
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Uncontrolled Keywords: long-term remission, acute myeloid leukemia, AML, cancers
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Academic Departments > Institute of Science and the Environment
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Depositing User: Steven Coles
Date Deposited: 13 Sep 2017 15:09
Last Modified: 14 Sep 2017 10:56

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