Integrating immunotherapy with targeted therapies in cancer treatment presents a novel combinatorial strategy where complementary modes of action of two distinct modalities suggest fascinating possibilities for therapeutic synergy. Strong line of evidence suggests that anti-tumor immunity is critical for clinical responses toward conventional and pathway-targeted cancer treatments. Immunotherapies may serve to consolidate the impressive clinical responses from targeted therapies into durable remissions via induction of long-lasting immune responses. The proposed research is based on our published and preliminary our data that define a novel Notch-mediated molecular mechanism of cancer-associated immunosuppression, combined with candidate systemic therapeutics, which overcomes this immunosuppression. We revealed that tumors and down-regulates expression of Delta-like (DLL) Notch ligand in the hematopoietic compartment, and the resulting decreased Notch activation leads to defects in T cells. Genetic or therapeutic enhancement of DLL1- mediated Notch signaling was sufficient to correct tumor-induced defects in T lymphocyte differentiation, improve T cell responses and memory, and produce significant tumor inhibition. We generated and tested in mouse tumor models a prototypic therapeutic reagent, soluble clustered (multivalent) DLL1, that demonstrated immune and therapeutic efficacy. Erlotinib, an inhibitor of EGF receptor (EGFR), has shown significant clinical responses and survival benefit in the treatment of in Non-Small Cell Lung Cancer (NSCLC), however disease recurrence remains a key outstanding problem. We hypothesize that adequate Notch signaling in the immune microenvironment is crucial for the induction of anti-tumor immunity and that ligand-specific pharmacological enhancement of Notch signaling can be exploited to significantly improve progression-free survival after EGFR-targeted therapy via induction of robust and long-lasting anti-tumor immune responses. We intend to test this idea in the following specific aims: 1) Determine the roles of Notch ligand expression in dendritic cells in the regulation of anti-tumor immune responses. 2) Evaluate the clinical efficacy of combination of anti-EGFR targeted therapy with pharmacologically enhanced DLL1/Notch signaling and the ability of multivalent DLL1 to rescues defective T cells, induce sustained immune responses, and durable remission. 3) Evaluate significance of Notch system in regulation of Th cell differentiation and induction of long-lasting remission in NSCLC patients after targeted therapy. We plan to focus on the above aims to achieve a molecular understanding of the role of Notch, DLL1 and other Notch ligands in anti-tumor immunity and to evaluate the therapeutic and prognostic potential that modulation and evaluation of this system could offer. The proposed pre-clinical studies will give us leads to enable the translation of these findings into clinically relevant therapeutics and prognostic assays.

Public Health Relevance

Strong line of evidence suggests that anti-tumor immunity is critical for clinical responses toward conventional and pathway-targeted cancer treatments. Our preliminary investigations identified tumor-induced alterations in Notch system in immune compartment as a novel mechanism of aberrant T cell differentiation and immunosuppression and proposed a new therapeutics to correct T cell defects in cancer. The current project is focused on understanding the roles of involved Notch ligands and testing a novel therapeutic intervention integrating the enhancement of hematopoietic Notch signaling and T cell-mediated immunity with targeted anti-EGF receptor therapy to translate the findings into potential therapeutic combination.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA175370-02
Application #
8743193
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Muszynski, Karen
Project Start
2013-09-26
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Uzhachenko, Roman; Boyd, Kelli; Olivares-Villagomez, Danyvid et al. (2017) Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis. Aging (Albany NY) 9:627-649
Pellom Jr, Samuel T; Singhal, Ashutosh; Shanker, Anil (2017) Prospects of combining adoptive cell immunotherapy with bortezomib. Immunotherapy 9:305-308
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Uzhachenko, Roman; Shanker, Anil; Dupont, Geneviève (2016) Computational properties of mitochondria in T cell activation and fate. Open Biol 6:
Uzhachenko, Roman; Shanker, Anil (2016) Notching tumor: Signaling through Notch receptors improves antitumor T cell immunity. Oncoimmunology 5:e1122864
Pulliam, Stephanie R; Uzhachenko, Roman V; Adunyah, Samuel E et al. (2016) Common gamma chain cytokines in combinatorial immune strategies against cancer. Immunol Lett 169:61-72
Shanker, Anil; Thounaojam, Menaka C; Mishra, Manoj K et al. (2015) Innate-Adaptive Immune Crosstalk. J Immunol Res 2015:982465
Uzhachenko, Roman; Shanker, Anil; Yarbrough, Wendell G et al. (2015) Mitochondria, calcium, and tumor suppressor Fus1: At the crossroad of cancer, inflammation, and autoimmunity. Oncotarget 6:20754-72

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