Microenvironment Produced by Acute Myeloid Leukemia Cells Prevents T Cell Activation and Proliferation by Inhibition of NF-κB, c-Myc, and pRb Pathways

Abstract

Tumors produce a variety of immunosuppressive factors which can prevent the proliferation and maturation of a number of normal hemopoietic cell types. We have investigated whether primary acute myeloid leukemia (AML) cells have an effect on normal T cell function and signaling. Tumor cell supernatant (TSN) from AML cells inhibited T cell activation and Th1 cytokine production and also prevented activated T cells from entering the cell cycle. These effects occurred in the absence of AML cell-T cell contact. We have demonstrated that AML TSN contained none of the immunosuppressors described to date, namely gangliosides, nitric oxide, TGF-β, IL-10, vascular endothelial growth factor, or PGs. Furthermore, IL-2 did not overcome the block, despite normal IL-2R expression. However, the effect was overcome by preincubation with inhibitors of protein secretion and abolished by trypsinization, indicating that the active substance includes one or more proteins. To determine the mechanism of inhibition, we have studied many of the major pathways involved in T cell activation and proliferation. We show that nuclear translocation of NFATc and NF-κB are markedly reduced in T cells activated in the presence of primary AML cells. In contrast, calcium mobilization and activation of other signal transduction pathways, namely extracellular signal-regulated kinase1/2, p38, and STAT5 were unaffected, but activation of c-Jun N-terminal kinase 1/2 was delayed. Phosphorylation of pRb by cyclin-dependent kinase 6/4-cyclin D and of p130 did not occur and c-Myc, cyclin D3, and p107 were not induced, consistent with cell cycle inhibition early during the transition from G0 to G1. Our data indicate that TSN generated by AML cells induces T cell immunosuppression and provides a mechanism by which the leukemic clone could evade T cell-mediated killing.

Tumor supernatant from myeloid malignancies inhibits T-cell apoptosis and cell cycle entry independently

“…It has been reported that malignant cells of both solid tumors and leukemias produce factors that inhibit cells of the immune system, which may help them evade immune surveillance. 1 In the present study, we examined whether the previously noted specific effects on T-cell cytokine production, cell cycle inhibition, pRb phosphorylation, c-Myc induction and apoptosis are exclusive to AML cells, or occur in other lower grade myeloid malignancies, namely MDS and chronic phase (CP) CML.…”

“…2 AML TSN prevents T-cell activation by profoundly inhibiting the production of the Th1 cytokines IFN-g and IL-2 and inhibits cell cycle entry before the G 0 -G 1 commitment point, 3 by preventing the phosphorylation of retinoblastoma protein (pRb) and the induction of c-Myc. 1 In addition, AML TSN delays the apoptosis of both normal hematopoietic and leukemic blast cells; 2 however, it was unknown as to whether this is a unique feature of AML or extended to other myeloid malignancies. We now show that T-cell apoptosis is inhibited by TSN from the cells of 11/12 cases of chronic myeloid leukemia (CML) and myelodysplastic syndrome (MDS) tested, irrespective of disease severity.…”

“…A number of malignancies such as melanoma, ovarian cancer, renal cell carcinoma and glioma produce an immunosuppressive microenvironment. 1 We have shown that acute myeloid leukemia (AML) tumor-derived supernatant (TSN) is immunosuppressive, preventing T-cell activation, proliferation and apoptosis. 2 AML TSN prevents T-cell activation by profoundly inhibiting the production of the Th1 cytokines IFN-g and IL-2 and inhibits cell cycle entry before the G 0 -G 1 commitment point, 3 by preventing the phosphorylation of retinoblastoma protein (pRb) and the induction of c-Myc.…”

Degradation of NF-κB in T Cells by Gangliosides Expressed on Renal Cell Carcinomas

“…Defective activation of NF-B has been reported in T cells from tumor-bearing mice and cancer patients (12)(13)(14). The deficiency stems from impaired nuclear localization of the RelA/p50 heterodimer, a problem that has been noted in both tumor-infiltrating lymphocytes (TIL) 3 and peripheral blood T cells isolated from patients with renal cell carcinoma (RCC) (15)(16)(17).…”

Dendritic cells in MDS and AML – cause, effect or solution to the immune pathogenesis of disease?

“…3,4,11 Even if a proportion of leukaemic cells were able to mature into normal functioning DC, the remaining leukaemic blasts in the microenvironment 12 may directly inhibit presentation of antigen to autologous T cells by an ill-defined contactindependent mechanism, although cytolytic function may be maintained. 13 Prior to the ability to distinguish T cells from B cells in blood lymphocytes, it was suggested that patients with AML were immunocompromised based on low numbers of circulating lymphocytes and suppressed DTH reaction to stimulus. 10 This study had led to the prevailing view of immune dysfunction in AML.…”