A Toll-like receptor (TLR) 5 agonist entolimod mediates anti-metastatic activity via NK cell-dependent T cell activation (TUM2P.1029)

Abstract

Abstract Directing innate immunity against cancer is a promising but poorly developed approach to immunotherapy due to the risk of acute inflammation induced by innate immunity activators. In this regard, TLR5 is a unique innate immune receptor with a distinct tissue specificity of expression and induction of a specific cytokine profile upon activation by its agonist bacterial flagellin that is significantly safer than that induced by other TLR agonists. Entolimod is an optimized Salmonella flagellin derivative with demonstrated safety and efficacy in protecting normal cells from stresses such as radiation or chemotherapy, while not protecting or stimulating tumors. We show here that systemic administration of entolimod has potent antitumor effects in mouse syngeneic colon (CT26) and breast (4T1) cancer models, including suppression of liver metastases and development of CD8 T cell memory. In these models, entolimod treatment leads to blood-borne homing of NK cells to the liver followed by activation of CD4 and CD8 T cells. Antibody-mediated depletion and adoptive transfer experiments showed that all three of these cell types are essential for entolimod’s antitumor effects and demonstrate a pivotal role for NK cell-mediated CD8 and CD4 T cell activation and formation of CD8 T cell memory. Therefore, entolimod has strong promise as a safe, effective and broadly applicable immunotherapeutic agent against liver metastases, which are currently a major cause of cancer-associated mortality.