Inhibition of CREB signaling through antagonism of vasoactive intestinal peptide enhances CD8 T cell function in a murine model of AML

Abstract

Abstract Signaling pathways that activate CREB may inhibit the potency of T cell responses following stimulation. One of the major mechanisms by which this occurs is the sequestration of CBP, which is also an NF-κB binding partner. One of the major molecules that signals through this pathway is vasoactive intestinal peptide (VIP). VIP is a 28 amino acid peptide that is secreted throughout the body by a variety of cell types including immune cells. VIP has shown to be a potent anti-inflammatory molecule with pleiotropic effects on T cells including cell cycle arrest and inhibition of cytokine secretion. The VIP signaling pathway represents a therapeutic target in disease settings in which a more robust T cell response would be beneficial. Acute myeloid leukemia (AML) is a hematological malignancy that has been explored as a candidate for a variety of T cell-based immunotherapies due to weak CD8 responses to AML blasts. We demonstrate here that administration of a hybrid peptide antagonist that blocks VIP signaling enhances CD8 T cell responses in a murine model of AML. CD8 T cells from treated mice showed enhanced secretion of IFN-γ and TNF-α as well as reduced expression of PD-1. These enhanced effector functions lead to a significant survival enhancement, which was lost when treated mice lacked T cells. Additionally, CD8 T cells from antagonist-treated survivors made up the majority of CD3+ cells following transfer to Rag1 knockout recipients. The phenotype of the cells was consistent with enhanced effector functions as transferred CD8+ T cells were predominately CD44+CD62L−. Taken together, these results demonstrate the potential for VIP antagonism as an immunotherapy strategy in settings of hematological malignancies.