Upregulation of the immunosuppressive cell surface glycoprotein, CD200, is a common
Upregulation of the immunosuppressive cell surface glycoprotein, CD200, is a common feature of acute myeloid leukemia (AML) and is associated with poor patient outcome. cell cytolytic activity. Together, these findings provide the first evidence that CD200 has a direct and significant suppressive influence on NK cell activity in AML patients and may contribute to the increased relapse rate in CD200+ patients. Keywords: CD200, natural killer cell, immunity, AML, CD200R, immunosuppression Introduction CD200 is a trans-membrane glycoprotein belonging to the type-1 immunoglobulin superfamily.1 In adults, CD200 is highly expressed in immune-privileged sites, such as the central nervous system, as well as leukocytes (including dendritic cells and T and B lymphocytes).2 In both mice and humans, interaction of CD200 with its receptor, CD200R, which is expressed on immune competent cells2 imparts an immunosuppressive signal leading to inhibition of macrophage function,3,4 induction of regulatory T cells,5 switching of cytokine profiles from Th1 to Th2 and inhibition of tumor-specific T-cell immunity.6 Consistent with this, CD200-deficient mice are susceptible to tissue-specific autoimmunity.4 The overexpression of CD200 has been implicated in the pathogenesis of solid tumors7,8 and hematological malignancies including acute myeloid leukemia (AML),9 lymphoma,10 chronic lymphocytic leukemia,11 hairy cell leukemia12 and myeloma.13 In addition, we have shown that CD200 upregulation in AML is a poor prognostic indicator in non-core binding factor leukemias.14 Recently, studies have demonstrated that expression of this protein is a common characteristic of cancer stem cells and is associated with tumor progression.15,16 Furthermore, CD200 has a central role in immune tolerance by protecting critical tissues and stem cells from immune damage, a characteristic that may be exploited to minimize graft rejection through selection of stem cells that have high CD200 expression.17,18 Therefore, these data are consistent with a hypothesis in which residual disease evades immune-recognition if CD200 is 117048-59-6 manufacture being expressed and indeed there is evidence that viruses encode CD200-type molecules as an immunoevasion strategy.19 In AML, there is 117048-59-6 manufacture evidence that a state of immunosuppression exists and that an anti-leukemia response can be effective in the treatment of residual disease.20-22 Natural killer (NK) cells, are important immune cells that modulate the initial recognition and clearance of virus-infected and malignant cells through the release of cytolytic vesicles.23-25 NK cells constitute approximately 10% of circulating lymphocytes in health and are identified generally as CD45+ + CD19? CD3? CD56+ cells. Their activation and immunosurveillance is tightly regulated through a complex network of cytokines and a large and diverse repertoire of membrane receptors that deliver both inhibitory signals (such as NKG2A/CD94 and KIRs) and stimulatory signals (such as NKG2D and the natural cytotoxicity receptors (NCRs): NKp30, NKp44 and NKp46) (Lakshmikanth et al.26; Hecht et al.27). It is therefore unsurprising that defective NCR expression and NK cell dysfunction has been associated with poor patient outcome in many cancers, including AML.28,29 Five distinct NK cell sub-populations have been identified based on expression of CD56 and CD16 (reviewed in Poli et al.,30): (1) CD56brightCD16? (normally~15% of NK cells), (2) CD56brightCD16+ (rare), (3) CD56dimCD16? (rare), (4) CD56dimCD16+ (~80%) and (5) CD56?CD16+ (rare). However, the frequency of these populations and their activating receptor repertoire/cytolytic 117048-59-6 manufacture activity remains to be elucidated within AML and the effect of CD200 expression on these parameters is unknown. Given the existing evidence that NK 117048-59-6 manufacture cell function influences AML blast clearance GP9 and long-term survival in AML, we investigated the possibility that CD200 expression may directly suppress anti-tumor immunity in this disease. We show that CD200hi AML patients have a reduced frequency of CD56dimCD16+ NK cells. Moreover, CD200hi AML patients display an NK cell phenotype that differs from CD200lo and are also dysfunctional in terms of service and effector action. Further, our findings suggest that CD200 manifestation on leukemic blasts have an influential part in suppressing NK cell cytolytic activity making CD200 a potential restorative target for CD200hi AML. Materials and methods Normal and AML patient sample materials Peripheral blood or bone tissue marrow samples were collected at analysis, before drug treatment and following educated consent from AML individuals 117048-59-6 manufacture treated in the UK Medical Study Council.