Cancer remains the leading cause of death with a disproportionate toll on minority communities. Most common cancers are refractory to traditional treatments. With recent appreciation of cancer immunosurveillance mechanisms, our long-term objective is to elucidate immune mechanisms of cancer regression and to develop immunotherapy approaches that can specifically eliminate malignant cells and provide durable benefits in cancer patients. Recent studies in various pathophysiological models of immune rejection, including cancer, suggest an indispensable co-operativity in adaptive and innate immune effector cells. Our work in a mastocytoma model demonstrated that CD8+ T cells provided a necessary """"""""help"""""""" to dormant natural killer (NK) cells in eliciting their antitumor function. This co-operativity of T cell and NK cell effector mechanisms led to complete tumor regression, by preventing the development of antigen-deficient tumor escape variants. A similar role of combined CD8+ T cells and NK cells was also observed by us in the rejection of mouse renal cell carcinoma Renca and by others in the control of mammary, bladder and intraperitoneal mesenchymal tumors. This signifies the importance of functional co-operativity of NK cells and T cells in tumor rejection. However, this protective team-work of T cells and NK cells fails in conditions of immunosuppressive chronic inflammation intrinsic to aggressive tumors as shown in inducible tumor models. Thus, it is imperative to investigate novel combinatorial therapeutic strategies and their mechanistic cross-talk to reduce tumor burden and potentiate anti-tumor immune effector functions by overriding tumor-induced immunosuppression. Based on our preliminary data, we hypothesize that combining tumor cell-death sensitizing bortezomib administration with adoptive NK cell transfer and immunostimulatory Notch activation should strengthen anti-tumor immune effector functions by modulating negative immune-regulatory circuits. This combinatorial strategy should overcome immunosuppressive effects of the chronic inflammation in tumor microenvironment and enhance therapeutic benefits against cancer. To test our hypothesis, we propose to address the following specific aims:
Aim 1 : Characterize the impact of bortezomib administration on tumor-infiltrating lymphoid and myeloid cells and their cytokine and chemokine production in the tumor microenvironment.
Aim 2 : Assess the effects of bortezomib on NK cell effector responses.
Aim 3 : Optimize NK cell adoptive therapy in combination with bortezomib and clustered multivalent DLL1 treatments in an established tumor. This proposal will be the first attempt at attacking the underexplored area of how anti-tumor functional co-operativity between the tumor- specific T cells and NK cells can be enhanced in the context of molecular targeting based on proteasome inhibition and immunostimulatory Notch signaling. The results will provide new insights for designing effective immunotherapy protocols relevant to cancers refractory to most conventional treatments and will have implications for pathophysiological conditions beyond cancer.

Public Health Relevance

This proposal will be the first attempt at attacking the underexplored area of how anti-tumor functional cooperativity between the tumor-specific T cells and NK cells can be enhanced in the context of molecular targeting based on proteasome inhibition and immunostimulatory Notch signaling.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Enhancement Award (SC1)
Project #
1SC1CA182843-01A1
Application #
8475316
Study Section
Special Emphasis Panel (ZGM1-TWD-9 (SC))
Program Officer
Wali, Anil
Project Start
2013-07-12
Project End
2017-06-30
Budget Start
2013-07-12
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$363,750
Indirect Cost
$113,750
Name
Meharry Medical College
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041438185
City
Nashville
State
TN
Country
United States
Zip Code
37208
Pellom Jr, Samuel T; Dudimah, Duafalia F; Thounaojam, Menaka C et al. (2017) Bortezomib augments lymphocyte stimulatory cytokine signaling in the tumor microenvironment to sustain CD8+T cell antitumor function. Oncotarget 8:8604-8621
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
Shanker, Anil; Thounaojam, Menaka C; Mishra, Manoj K et al. (2017) Innate-Adaptive Immune Crosstalk 2016. J Immunol Res 2017:3503207
Pellom Jr, Samuel T; Singhal, Ashutosh; Shanker, Anil (2017) Prospects of combining adoptive cell immunotherapy with bortezomib. Immunotherapy 9:305-308
Uzhachenko, Roman; Shanker, Anil (2016) Notching tumor: Signaling through Notch receptors improves antitumor T cell immunity. Oncoimmunology 5:e1122864
Clark, Ryan S; Pellom, Samuel T; Booker, Burthia et al. (2016) Validation of research trajectory 1 of an Exposome framework: Exposure to benzo(a)pyrene confers enhanced susceptibility to bacterial infection. Environ Res 146:173-84
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
Lawrence, Shanieek; Pellom Jr, Samuel T; Shanker, Anil et al. (2016) Tributyltin exposure alters cytokine levels in mouse serum. J Immunotoxicol 13:870-878
Uzhachenko, Roman; Shanker, Anil; Dupont, Geneviève (2016) Computational properties of mitochondria in T cell activation and fate. Open Biol 6:
Pulliam, Stephanie R; Pellom Jr, Samuel T; Shanker, Anil et al. (2016) Butyrate regulates the expression of inflammatory and chemotactic cytokines in human acute leukemic cells during apoptosis. Cytokine 84:74-87

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