Transforming Growth Factor-Beta (TGF-?) has profound immunosuppressive effects on a variety of immune cells. Natural killer (NK) cells are large granular lymphocytes that constitute a vital component of the innate immune system. NK cells produce abundant interferon gamma (IFN-?) to enhance tumor cell recognition and destruction, and to clear viral infection, including herpes simplex oncolytic viruses (OVs) in glioblastoma (GBM) treatment. Due to its complexity, TGF-? signaling has not been fully characterized. It also remains to be determined whether TGF-? itself or TGF-? signaling can be modulated to control NK cell functions in order to better control tumor progression and to enhance OV therapeutic efficacy in GBM. We hypothesize that TGF-? signaling can be further elucidated and modulated in NK cells to better understand cancer progression and enhance cancer treatment. Our goal is to investigate the molecular basis of how TGF-? suppresses NK anti-tumor activity by identifying the elements directly involved in this process, and to study the potential to increase the signaling to improve NK anti-tumor activity, but to decrease NK activity by pre-TGF-? treatment in the context of OV therapy, where NK cells limit OV expansion and therapeutic efficacy. Our proposed studies have a great potential to advance GBM treatment and/or GBM prevention and make us understand more about tumor and virus recognition and destruction. We will test our hypothesis through three Aims: 1) To determine the molecular basis of transcriptional repression of NK cell function by TGF-?;2) Can we disrupt TGF-? signaling to increase immune responses, and, in turn, to control GBM progression in vivo? 3) To augment TGF-? signaling in NK cells to enhance OV therapy efficacy in GBM.

Public Health Relevance

Glioblastoma (GBM) is the most common and aggressive brain tumor in humans. Although we have researched it for decades, survival time of patients suffering from GBM remains extremely poor. In this application, our first goal is to understand a very important negative signaling initiated by a cytokine, TGF-?. The other goal of this application is to either inhibit or enhance this signaling especially in NK cells at different contexts to treat GBM using our excellent animal models. Eventually, our long-term goal is to apply these studies in patients when we prove they are effective and safe.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA155521-03
Application #
8710094
Study Section
Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
Program Officer
Yovandich, Jason L
Project Start
Project End
Budget Start
Budget End
Support Year
3
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
Chen, Xilin; Han, Jianfeng; Chu, Jianhong et al. (2016) A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. Oncotarget 7:27764-77
Chen, Luxi; Yu, Jianhua (2016) Modulation of Toll-like receptor signaling in innate immunity by natural products. Int Immunopharmacol 37:65-70
Han, Jianfeng; Alvarez-Breckenridge, Christopher A; Wang, Qi-En et al. (2015) TGF-β signaling and its targeting for glioma treatment. Am J Cancer Res 5:945-55
Zhao, Ran; Cui, Tiantian; Han, Chunhua et al. (2015) DDB2 modulates TGF-β signal transduction in human ovarian cancer cells by downregulating NEDD4L. Nucleic Acids Res 43:7838-49
Han, Jianfeng; Chen, Xilin; Chu, Jianhong et al. (2015) TGFβ Treatment Enhances Glioblastoma Virotherapy by Inhibiting the Innate Immune Response. Cancer Res 75:5273-82
Ren, Yulin; Yuan, Chunhua; Deng, Youcai et al. (2015) Cytotoxic and natural killer cell stimulatory constituents of Phyllanthus songboiensis. Phytochemistry 111:132-40
Deng, Youcai; Kerdiles, Yann; Chu, Jianhong et al. (2015) Transcription factor Foxo1 is a negative regulator of natural killer cell maturation and function. Immunity 42:457-70
Deng, Youcai; Chu, Jianhong; Ren, Yulin et al. (2014) The natural product phyllanthusmin C enhances IFN-γ production by human NK cells through upregulation of TLR-mediated NF-κB signaling. J Immunol 193:2994-3002
Yoo, Ji Young; Hurwitz, Brian S; Bolyard, Chelsea et al. (2014) Bortezomib-induced unfolded protein response increases oncolytic HSV-1 replication resulting in synergistic antitumor effects. Clin Cancer Res 20:3787-98
Kim, Tae Hyong; Song, Jieun; Kim, Sung-Hak et al. (2014) Piperlongumine treatment inactivates peroxiredoxin 4, exacerbates endoplasmic reticulum stress, and preferentially kills high-grade glioma cells. Neuro Oncol 16:1354-64

Showing the most recent 10 out of 27 publications