Abstract A9: Pharmacological stimulation of DLL1-Notch signaling as an antitumor immunotherapy

Abstract

Abstract Deficiencies in immune function are one of mechanisms for tumor escape from host immune surveillance, and therapies aimed at overcoming these defects are of major importance in cancer immunotherapy. However, the underlying causes of these defects are multiple and remain not fully understood. We report a previously undescribed mechanism for tumor-associated defects in T cell function mediated by reducing levels of Delta-like (DLL) 1 and DLL4 in the hematopoietic microenvironment, and show that elevated levels of circulating vascular endothelial growth factor (VEGF) characteristic for cancer patients is one of the mediators of this effect. Remarkably, selective activation of DLL1-Notch signaling alone by over-expression of DLL1 in bone marrow precursors or by soluble multivalent DLL1 treatment significantly enhances tumor-specific immune responses and inhibits tumor growth in multiple tumor models. The data suggest that tumor growth suppresses T cell differentiation and function via inhibition of DLL-mediated Notch signaling in the hematopoietic compartment. Our findings uncover a novel molecular mechanism of immune suppression and suggest a pharmacologic intervention based on activation of DLL1-Notch signaling to reverse this effect, stimulate immune responses and suppress tumor growth. Given that recently DLL1 was also implicated in abnormal tumor vessel formation and growth inhibition [Zhang JP, ea. Cancer Lett. 2011;309:220–227], systemic stimulation of Notch by multivalent DLL1 might represent an efficient therapeutic strategy targeting multiple mechanisms of tumor growth.