Mutant KRAS promotes NF-κB driven CCL20 chemokine expression in pancreatic ductal adenocarcinoma

ABSTRACT The chemokine CCL20 is implicated in inflammation and cancer but has proven challenging to target therapeutically. In this study, we precisely define what cells produce CCL20 in pancreatic inflammation and cancer. Through analysis of single cell RNA data, mutation and copy number signatures, gene methylation, and in vitro studies, we show that CCL20 and other NF-κB driven chemokine production is largely dependent on oncogenic KRAS in the malignant pancreas. Blockade of CCL20-CCR6 signaling in vivo using a novel partial agonist inhibitor, CCL20LD, increased recruitment of antigen presenting cells without significantly impinging tumor growth. Lastly, resistance to pan-RAS or allele-specific KRAS inhibitors decreased CCL20-dependent immune recruitment in culture. These results suggest that oncogenic KRAS activates NF-κB signaling in human pancreas cancer, resulting in pharmacologically reversible changes to chemokine production that may participate in immune suppression or immune evasion within the pancreas cancer microenvironment.