Abstract 3642: Cancer therapy by resuscitating Notch immune surveillance

Abstract

Abstract The immunosuppressive tumor microenvironment perturbs numerous immune regulatory networks and usurps host anti-tumor immunity. We discovered that tumor interferes with host hematopoietic Notch system in lung cancer patients. The resultant decrease in immune Notch signaling could be a major causative link in the inadequate induction of anti-tumor immunity. Interestingly, we found that tumor-induced decrease in immune Notch in various mouse solid tumor models could be restored therapeutically by the following two agents. Administration of a novel Delta-like ligand 1 (DLL1) multivalent cluster and the FDA-approved proteasome inhibitor drug bortezomib - which also sensitizes tumors to death signals - could activate Notch 1 signaling in lymphoid cells of tumor-bearing mice without increasing tumor cell proliferation or clonogenicity. Systemic activation of DLL1-Notch signaling could attenuate tumor vascularization as well as increase T cell infiltration in tumor, decrease proportion of regulatory T cells and enhance antitumor T cell function and memory in multiple mouse tumor models. New data also show that bortezomib affects the expression of notch receptors and ligands differentially in lymphocytes and in a wide range of solid tumor cells. Moreover, bortezomib administration increased the expression of Notch target genes Hes 1 and Hey 1 in thymus, lymph node, and spleen, as well as decreased the proportion of regulatory T cells and enhanced T cell production of IFN-γ in tumor-bearing mice. Results indicate that bortezomib-induced activation of Notch target genes Hes 1 and Hey 1 is through its inhibition of NFkB while its activation of another Notch target gene Deltex 1 is mediated via PI3K. The findings suggest a potential synergistic action of bortezomib and DLL1 activation of Notch signaling. The potential of modulating anti-tumor Notch signaling by the prototypic DLL1 cluster in combination with bortezomib presents exciting opportunities to uncover multi-pronged immune stimulatory regimens. Therapeutic restoration of immune Notch signaling could provide effective treatment and recurrence-free survival in cancer patients by breaking tumor resistance, enhancing immune surveillance, and sustaining robust anti-tumor immunity. Citation Format: Duafalia F. Dudimah, Samuel T. Pellom Jr., Roman V. Uzhachenko, David P. Carbone, Mikhail M. Dikov, Anil Shanker. Cancer therapy by resuscitating Notch immune surveillance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3642. doi:10.1158/1538-7445.AM2014-3642