3039 – SYMPATHETIC NERVES AND REACTIVE OXYGEN SPECIES REGULATE INNATE AND ADAPTIVE IMMUNE FUNCTION IN THE LEUKEMIC MICROENVIRONMENT

Abstract

Acute myeloid leukemia (AML) is an acquired hematological malignancy resulting in the expansion of undifferentiated leukemic blasts at the expense of healthy hematopoiesis. The sympathetic nervous system (SNS) plays a key role in regulating leukemogenesis, but the precise mechanism remains unclear. We have found that in a mouse model of MLL-AF9-driven AML, ROS levels in the leukemic niche are elevated, particularly in myeloid-lineage cells. Treatment with antioxidants or genetically targeting NADPH Oxidase (NOX)-derived ROS prolonged survival and reduced leukemic burden. Inhibiting ROS in AML resulted in higher levels of CD8 cytotoxic T cell activation, suggesting that niche-derived ROS may suppress T cell activity. We hypothesize that this occurs due to a loss of sympathetic nerves. Indeed, chemical sympathectomy increased myeloid-derived ROS and reduced CD8 T cell activation in healthy and leukemic mice, and leukemic mice devoid of β2 adrenergic signaling had fewer total CD8 T cells and higher leukemic burden. The precise cell types suppressing CD8 T cells via ROS are likely to be myeloid lineage cells. Macrophages, neutrophils, and myeloid-derived suppressor cells express high levels of NOX, generate the highest levels of ROS during leukemia, and are implicated in the suppression of lymphocyte activation in other malignancies. The loss of sympathetic nerves in the bone marrow and CD8 T cell dysfunction, both which occur in patients, may be linked. Indeed, our data point to a role for the loss of SNS activity during leukemia as a driver of NOX-derived ROS production by myeloid cells and suppression of CD8 T cell responses. Promoting these beneficial neuro-immune interactions could help boost anti-AML immunity and improve survival in AML patients.