Abstract
Background and Aims: Although leukemic cells express tumor-associated antigens, suppression of an effective T cell immune response is a well known phenomenon in acute myeloid leukemia (AML). In principle, the malignant cells may escape immune surveillance by (1) incomplete T cell activation due to the absence of costimulatory molecules on the leukemic cell types, (2) secretion of soluble immunosuppressive factors, which may lead among others to (3) induction of anergic and/or regulatory T cell phenotypes. A better understanding of the underlying mechanism would have important implications for the development of immunotherapeutic strategies.
Methods: CD3+ T cells were analyzed for activation, proliferation and Th1 cytokine production after coculturing with primary AML cells or leukemic cell supernatant. In addition, self-developed human Treg microarrays were used to reveal a gene expression profile of CD4+ T cells isolated from untreated AML patients (n=7) in comparison to CD4+ T cells from healthy volunteers (n=6) and AML patients after achieving a complete remission (n=4). The specific regulation of selected canditate genes was confirmed by realtime RT-PCR. Based on microarray results cell-cycle analyses were performed in order to study the effect of primary AML cells on the cell-cycle progression of stimulated T-cells.
Results: Our studies could show that primary AML cells suppress T cell activation, proliferation and Th1 cytokines production mainly in a cell-contact dependent manner and to a minor degree via soluble factors. Nevertheless, cell-cycle analyses demonstrated that soluble factors from leukemic cell supernatants may inhibit the cell-cycle entry of T cells after mitogenic stimulation with an arrest in G0/G1 phase. Interestingly, the molecular profile of CD4+ T cells isolated from untreated AML patients could identify a profound dysregulation of molecules involved in the regulation of cell-cycle (i.e., CDK4, Vav2, Egr-1, Id2) and apoptosis (i.e., Bcl-2, Bax). In addition, genes important for the immune response (i.e., IL2R, CTLA-4), especially various chemokines/-receptors (i.e., RANTES, CXCL10, CCR2) were dysregulated, whereas the expression pattern of genes specific for regulatory T cells (i.e., FoxP3, PD-1, GITR) were broadly unaffected.
Conclusion: AML cells (in-)/directly modulate normal T cell function such as activation, proliferation, cytokine/chemokine production and cell-cycle regulation. One might speculate that the lack of an effective anti-tumor response is associated with a cell-cycle arrest resulting in T cell anergy. Cell-cycle regulators may serve as potential targets for novel immunotherapeutic strategies to eradicate minimal residual disease in patients with AML.
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