Microenvironment produced by acute myeloid leukemia cells prevents T cell activation and proliferation by inhibition of NF-kappa B, c-myc, and pRb pathways

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 ha ve an effect on normal T cell function and signaling. Tumor cell supernatan t (TSN) from AML cells inhibited T cell activation and Th1 cytokine product ion and also prevented activated T cells from entering the cell cycle. Thes e effects occurred in the absence of AML cell-T cell contact. We have demon strated that AML TSN contained none of the immunosuppressors described to d ate, namely gangliosides, nitric oxide, TGF-beta, IL-10, vascular endotheli al growth factor, or PGs. Furthermore, IL-2 did not overcome the block, des pite normal IL-2R expression. However, the effect was overcome by preincuba tion with inhibitors of protein secretion and abolished by trypsinization, indicating that the active substance includes one or more proteins. To dete rmine the mechanism of inhibition, we have studied many of the major pathwa ys involved in T cell activation and proliferation. We show that nuclear tr anslocation of NFATc and NF-kappaB are markedly reduced in T cells activate d in the presence of primary AML cells. In contrast, calcium mobilization a nd activation of other signal transduction pathways, namely extracellular s ignal-regulated kinase1/2, p38, and STAT5 were unaffected, but activation o f 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 G(0) to G(1). Our data indicate that TSN generat ed by AML cells induces T cell immunosuppression and provides a mechanism b y which the leukemic clone could evade T cell-mediated killing.