Abstract B079: Comprehensive expression atlas of chemokine ligands and receptors reveals endothelial ACKRs as regulators of immune exclusion in human PDAC

Abstract

Pancreas cancer remains a devastating disease with an immunologically cold microenvironment that resists immunotherapies. Because immune cell recruitment is dependent on chemokine signaling, clinical trials targeting chemokine receptors have shown limited benefit due to signaling redundancy. We hypothesized that the chemokine availability to the receptors may be altered by Atypical Chemokine Receptors (ACKRs), which scavenge chemokines without inducing downstream signaling and contribute to immune exclusion in PDAC. Using transcriptomic profiling, we generated a comprehensive atlas of classical ligands and receptors and ACKRs, where we discovered ACKR expression is enriched in endothelial cells, which exhibited higher incoming signaling than immune cells. Among all ACKRs, ACKR1, expressed in tumor-associated venous endothelium, was most abundant and interact with most of the chemokines. We validated ACKR1 expression and showed strong spatial association with multiple ACKR1 binding ligands that compete with canonical receptors for ligand binding. Together, these findings indicate that rewired chemokine signaling may influence pancreas cancer progression not only by modulating ligand production but also reprogramming receptor-mediated gradient control mechanisms. Pronounced ACKR expression suggests an underappreciated role for tumor-associated vasculature in shaping chemokine communication networks and modulating the immune microenvironment in pancreas cancer.