TAMing Colitis and Colitis-Associated Colon Cancer

Abstract

Inflammatory Bowel Diseases (IBD) are chronic, relapsing, inflammatory disorders characterized by a robust cytokine-driven inflammation of the gut. This chronic inflammation leads to significant morbidity and mortality, including an increased risk for colorectal cancer. Using a combination of mouse models and analyses of human samples, we show that the receptor tyrosine kinases (RTK) Axl and Mer, members of the TAM subfamily, and their ligand Protein S (Pros1) mediate an anti-inflammatory response that is fundamental for preventing colitis. Furthermore, in marked contrast to the reported oncogenic function of Axl and Mer in tumors, genetic ablation of Axl and Mer in mouse models promotes colitis-associated colon cancer. Axl−/−Mer−/− mice develop an exacerbated inflammatory response to Dextran Sulfate Sodium (DSS)-induced colitis, as determined by colonoscopy score, histopathological analysis and inflammatory profile of lamina propria leukocytes. Axl−/−Mer−/− mice develop an increase number and larger polyps than wild type (WT) mice upon azoxymethane (AOM)-DSS treatment. Axl and Mer are expressed in intestinal macrophages upon inflammation and Axl−/−Mer−/− macrophages produce higher levels of pro-inflammatory cytokines in response to intestinal injury than WT controls. Furthermore, the TAM agonist Pros1 is essential for limiting the pathological activation of macrophages and induced colitis. Pros1 is expressed in activated T cells and functions to dampen the inflammatory response in macrophages through Axl and Mer. Transfer of Pros1−/− naïve T cells into Rag1−/− mice leads to acceleration of colitis in comparison to WT naïve T cells. Remarkably, IBD also shows a significant association with PROS1 deficiency. Patients with active IBD more frequently showed lower levels of plasma PROS1 in comparison to healthy controls. Therefore, our results identify the TAM RTKs and their ligand Pros1 as a hitherto unknown mechanism for the prevention of pathological inflammation in the intestine. While TAM inhibitors have been identified as prospective candidates for molecular anti-cancer therapeutics, the beneficial anti-inflammatory effects of the TAM pathway present a paradox at least in the context of colitis-associated colon cancer. Future efforts in TAM-based therapeutics would benefit from comprehensive understanding of TAM function both in cancer cells and in the tumor microenvironment.