Abstract
Abstract Notch signaling plays diverse roles in lymphocyte differentiation and tumor angiogenesis. Our recent findings implicate the role of the Notch 1 pathway in promoting antitumor immune effector functions. We explored the effects of Notch 1 stimulation on T cell immunity and its potential pharmacological activation using multivalent Delta-like Notch 1 ligand DLL1 cluster in combination with the proteasome inhibitor bortezomib, which could stabilize Notch 1 activation. Bortezomib was found to selectively sensitize solid tumor cells to apoptosis by upregulating death receptors on tumor cells and amplifying caspase-8 activation in the death-inducing signaling complex. This resulted in reduced pulmonary nodules of injected tumor cells in mice. Additionally, in an in vivo tumor setting, no adverse effects of bortezomib were observed on the antigen-specific T cell proliferative or cytolytic functions. But no long-term survival benefits could be obtained, possibly due to the immunosuppressive effects of the tumor. In our more recent studies, we observed that DLL1-specific immune Notch activation could enhance antitumor T cell immunity by overcoming tumor-associated immunosuppression in D459 and Lewis lung carcinoma models. The results offer a novel combinatorial approach to abrogate the immunosuppressive circuitries operating in the tumor microenvironment with a potential to reduce tumor burden and resuscitate tumor-specific immunity. This work has important translational implications for improving immunotherapy in cancer patients, and may provide insights into new strategies for cancer prevention. Citation Format: Duafalia F. Dudimah, Roman V. Uzhachenko, Samuel T. Pellom, Jr., Asel K. Biktasova, Mikhail M. Dikov, David P. Carbone, Anil Shanker. Resuscitating cancer immunosurveillance by combining Notch 1 and death receptor-activating therapy. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B93.
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