Abstract 3983: Resuscitating immune surveillance in cancer.

Cancer growth interferes with the Notch signaling that plays diverse roles in lymphocyte commitment and differentiation, oncogenesis, and peripheral immune responses. Our studies show that the stimulation of hematopoietic Notch signaling following administration of a prototypic therapeutic agent clustered multivalent Delta-like Notch ligand (DLL1), in mouse lung tumor models can correct tumor-induced defects in lymphocyte differentiation and improve antitumor lymphocyte responses, without increasing tumor cell proliferation. Moreover, since the Notch signaling complex is inactivated via the proteasome, its inhibitor bortezomib, amongst its other potential effects, may sustain DLL1-mediated pharmacological activation of the Notch signaling. Our data demonstrate that the proteasome inhibitor bortezomib can selectively sensitize solid tumors to apoptotic signals by upregulating death receptors on tumor cells and amplifying caspase-8 activation in the extrinsic cell death pathway, without any adverse effect on the antigen-specific T cell proliferative or cytolytic functions in an in vivo setting. In the current study, we investigated the effects of bortezomib and DLL1 on Notch receptor/ligand system and its downstream signaling network with an aim to enhance cancer immunotherapy. Results show that bortezomib affects the expression of notch receptors and ligands differentially in lymphocytes and in a wide range of solid tumor cells: 4T1, PyMT, MDA-MB-231, C26, LLC, D459, and Renca-HA. Specifically, the expression of Notch 4 receptor and its ligand Jagged 1 was reduced in bortezomib-treated tumor cells. In addition, bortezomib treatment of tumor cells modulated Notch downstream targets Hes1, Hes3, Hey1, Deltex1 and Deltex3, which act as transcriptional regulators of tissue-specific differentiation. bortezomib also modulated the phosphorylation of Erk1/2 MAP kinases and AKT suggesting that bortezomib may mediate its effects through downstream phosphorylation of Erk targets, such as STATs and NFkB, or PI3K, which are key players in signaling cross-talk and intersect with Notch signaling. Noreover, bortezomib administration increased the expression of Notch target Hes1 in thymus, lymph node and spleen of tumor-bearing mice, suggesting a potential synergistic action of bortezomib and DLL1 activation of Notch signaling. These results suggest that tumor cell-death sensitizing bortezomib and pharmacological DLL1 cluster activating immunostimulatory Notch in tumor-bearing host follow common signal transduction pathways and can synergize in antitumor activity. These findings offer a novel three-pronged combinatorial therapeutic approach of immunostimulatory Notch ligand DLL1 and bortezomib to abrogate the immunosuppressive circuitries operating in the tumor microenvironment with a potential to reduce tumor burden and resuscitate tumor-specific immunity. Citation Format: Duafalia F. Dudimah, Roman V. Uzhachenko, Samuel T. Pellom, Asel K. Biktasova, Mikhail M. Dikov, David P. Carbone, Anil Shanker. Resuscitating immune surveillance in cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3983. doi:10.1158/1538-7445.AM2013-3983