Down-regulation of signal transducer and activator of transcription 3 improves acute myeloid leukemia-derived dendritic cell function
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The only successful immunologic therapy in acute myeloid leukemia (AML) is allogeneic transplantation, however this approach has limitations. Therefore autologous therapies, including stimulating the patients’ immune system with AML-derived dendritic cell (DC) vaccines, are being sought. Clinically these vaccines have proven to be less successful than anticipated. We have previously shown that constitutive signal transducer and activator of transcription (STAT) 3 activity is present in the blasts of approximately half of AML patients and correlates with poor prognosis. STAT3 regulates a variety of cellular events and has been shown to play a role in immuno-suppression by inhibiting DC differentiation, resulting in induction of T cell tolerance. Taken together, we hypothesize that AML-DC with constitutive STAT3 activity will have impaired ability to fully differentiate and efficiently stimulate T cells. Methods. STAT3 inhibitory shRNAmirs and four JAK/STAT inhibitors (AG490, arsenic trioxide (ATO), JSI-124 and NSC-74859) were studied on AML-DCs from two cell lines, ten patient samples and three cord blood samples. Results. AML blasts differentiated to DCs regardless of the level of activated STAT3, however AML-DC with high levels of activated STAT3 elicited less T cell response than AML-DC with low levels of activated STAT3. AML blasts transduced with STAT3 shRNAmir and differentiated to DCs formed functional AML-DC that increased stimulation of allogeneic T cells compared to control DCs in 4/4 patient samples without affecting immunophenotype or endocytotic activity. While the inhibitors were unable to enhance the early differentiation phase of DC development, when dosed during the last 24 hours of maturation, ATO led to enhanced T cell stimulation of in 2/2 AML cell lines and 8/9 patient samples compared to controls (p=0.0001), while having a minimal effect on cord blood-derived DC. ATO-treated AML-DCs had an increased number of cells expressing mature DC markers and supernatants from treated DCs contained higher amounts of the T cell stimulating cytokine IL-12p40. These data demonstrate that AML-DCs have improved immunogenicity after reducing STAT3 protein levels during differentiation. Further, the observation that treatment with ATO is superior to the more targeted JAK/STAT inhibitors, suggests that DC maturation is not solely regulated by STAT3.