Abstract 1624: NOTCH ligand-based therapeutics for immunomodulation in cancer and organ transplantation

Abstract

Abstract We demonstrated in human and mouse studies that tumor-induced modulation of Notch ligand expression and Notch signaling in hematopoietic compartment contributes to tumor immune escape. Down-regulation of delta-like ligands (DLL) leads to defects in T cell development and T helper (Th1) cell differentiation with the prevalence of regulatory T cell (Treg) generation. To determine the roles of Notch ligands in antigen-presenting dendritic cells in regulation of antitumor immune responses we generated a set of lineage-specific knock-out mice lacking one of the Notch ligands in CD11c+ dendritic cells (DC). We are developing and testing a set of reagents for clinical application for ligand-specific activation or inhibition of Notch signaling to stimulate or inhibit, respectively, various types of immune responses for applications in oncology and immune diseases. Mice with DLL1 insufficiency in DC demonstrated remarkably accelerated growth of Lewis lung carcinoma (LLC) tumor, and reduced survival compared to wild type animals. This associated with impaired anti-tumor immune responses indicated by the decreased tumor infiltration by IFNγ-producing T cells. Jagged2 knockout did not cause any significant alterations. Notch ligand expression in antigen-presenting cells was identified as a “checkpoint” regulating the type of immune response. Data reveal that expression of Notch ligands by antigen-presenting cells is an important immune response specifying mechanism and that ligand-specific Notch signaling could be a valuable therapeutic target. Reagents for the pharmacological modulation of immune responses based on Notch ligand constructs is proposed. Our cell-based study showed that pharmacological activation of Notch ligands required multivalent receptor-ligand interaction, whereas soluble ligands acted as competitive Notch inhibitors. We have generated reagents that comprise specific domains of the DLL1 in multivalent or monovalent form. Therapeutic inhibition of Notch by monovalent DLL1-based reagent accelerated LLC tumor growth and attenuated T cell-mediated anti-tumor immune response. In a heart transplantation mouse model, monovalent DLL1 reagent significantly prolonged allograft survival by inhibiting Th1 effector and memory T cell differentiation. Multivalent forms of DLL1 effectively stimulated Notch signaling in T cell cultures and enhanced IFNγ production, whereas monovalent reagent had opposite effects. Pharmacological up-regulation of DLL1-mediated Notch signaling with multivalent forms of ligand represents an efficient strategy for the enhancement of anti-tumor immunity and targeting multiple mechanisms of tumor growth. Monovalent DLL1 forms could be utilized for therapeutic inhibition of Th1 responses in autoimmune diseases and organ transplantation. Reagents based on the mono- and multivalent forms of Notch ligands can be efficiently utilized for therapeutic modulation of Notch signaling. Note: This abstract was not presented at the meeting. Citation Format: Elena I. Tchekneva, Anneliese E. Antonucci, Irina Chekneva, Nicholas Long, Jason V. Evans, Anwari Akhter, David P. Carbone, Thomas Magliery, Mikhail M. Dikov. NOTCH ligand-based therapeutics for immunomodulation in cancer and organ transplantation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1624. doi:10.1158/1538-7445.AM2017-1624