1347 VIP Biology drive prognosis in AML patients

<h3>Background</h3> Despite the initial efficacy of intensive chemotherapy regimens in inducing remission in acute myeloid leukemia (AML) patients, relapse occurs in most patients and highlight the pressing need for a molecularly informed therapeutic strategy to effectively treat AML. Vasoactive Intestinal Polypeptide (VIP) is a 28 amino acid peptide interacting with two types of receptors, VPAC1/VPAC2 to drive immunosuppression in T cells and monocytes. We hypothesized that specific antagonists of VIP-VPAC signaling biology could function as immune checkpoints drugs to treat AML. <h3>Methods</h3> Repository of publicly available AML patients on cBioportal were utilized to interrogate the associations of VIP/VPAC expression on AML survival and the constituents of the tumor microenvironment (TME). Preclinical experiments were performed in C1498 models and bone marrow derived macrophages (BMDM) to dissect mechanistic relevance of VIP/VPAC in AML. <h3>Results</h3> Our immune profiling and bioinformatics analysis showed an enrichment of VIP expressing PBMC in AML patients as compared to healthy volunteers (figure 1A) that correlates to blast markers (figure 1B) and driving AML mortality (figure 1C). VPAC1/2 were highly expressed in myeloid cells of AML patients (figure 2). <i>In vitro</i> characterization experiments demonstrated VPAC1 on immunosuppressive myeloid cells whereas VPAC2 on anti-tumor like myeloid cells (figure 3). Corroborating, bioinformatics analysis revealed positive correlation between VPAC1 and myeloid suppressive marker, CD33. VPAC2 positively correlated to T cells marker, CD8. Additionally, VPAC1 inversely correlated to VPAC2 (figure 4). Surprisingly, VPAC2 expression associated with better AML survival relative to low VPAC2 expression, particularly in high VIP expressing patients. In absence of VPAC2, high VIP expressing AML patients had worst survival as compared to low VIP subsets, suggesting that VIP interaction with VPAC1 is driving poor prognosis in absence of VPAC2 existence in the TME (figure 5). In parallel, genetic (figure 6A) or pharmacological abrogation (figure 6B) of VPAC1/2 improved survival of AML bearing mice, highlighting a need of VPAC2 expressing populations for seeding anti-tumor response that can be accentuated with VPAC inhibition. <h3>Conclusions</h3> VIP is a negative prognostic indicator in AML and correlated with expression of CD34 in AML. Up-regulation of VIP receptors seen in T cells and monocytes in the AML TME. Preclinical data support the anti-leukemia efficacy of dual-targeting of VIP receptor signaling in AML.