Natural killer (NK) cells are a critical component of innate immunity and are cytolytic to tumor cells and viral- infected cells. Oncolytic herpes simplex virus 1 (oHSV), which has recently been approved by the FDA for the treatment of cancer, holds great potential in the treatment of glioblastoma (GBM), a highly lethal brain tumor. However, based on our previous studies, host NK cells provide a rapid and robust response following central nervous system (CNS) infection with oHSV, thus presenting a barrier for effective oncolytic virotherapy for GBM. Cytotoxic genes, including granzyme B (Gzmb), determine NK cell cytolytic activity in these settings; however, the molecular mechanisms responsible for regulating Gzmb expression are largely unknown. In this application, our preliminary data show that Smad4, a co-Smad protein in the TGF-beta superfamily signaling pathway, positively regulates Gzmb expression in a TGF-beta-independent manner, which correlates with decreased anti-tumor activity in mice with an NK-specific Smad4 deficiency. Using this mouse model, we also discovered that Smad4 positively regulates NK cell homeostasis and maturation by upregulating Blimp1, a positive regulator of NK cell maturation. Smad4 is also a co-Smad in bone morphogenetic protein (BMP) signaling. Our preliminary data support the hypothesis that the TGF-?-independent role of Smad4 in regulating NK cell function is downstream of BMP signaling, which has been reported to positively regulate NK cell function. Here, we propose to explore the mechanisms for this conceptually novel discovery and to modulate BMP-Smad4 signaling in NK cells in the setting of oncolytic virotherapy for GBM. Our overall hypothesis is that Smad4 positively regulates NK cell development and cytotoxicity against target cells including oHSV-infected GBM cells, and this can be modulated by temporarily inhibiting BMP-Smad4 signaling to enhance the efficacy of oHSV therapy. We propose an in-depth investigation into the molecular mechanisms whereby smad4 positively regulates Gzmb expression, cytotoxicity, and development of NK cells in mice using our aforementioned animal model and in humans using samples of patients with familial juvenile polyposis (FJP), having a germline loss-of-function mutation in Smad4. Additionally, we also propose to modulate BMP- Smad4 signaling to temporarily inhibit NK cell responses to oHSV to enhance its efficacy for the treatment of GBM. These are outlined in three Aims to test our hypothesis.
Aim 1 is to dissect the mechanisms by which Smad4 positively regulates NK cell cytotoxicity against target cells.
Aim 2 is to characterize the mechanisms by which Smad4 positively regulates NK cell development.
Aim 3 is to temporarily inhibit BMP-Smad4 signaling in NK cells to improve oncolytic viral therapy for GBM in vitro and in vivo. We believe that the results of these studies will lend new insights into basic mechanisms of cytotoxic cell therapy and that exploration of novel therapeutics in preclinical models will advance the treatment of GBM.

Public Health Relevance

Despite surgery, chemotherapy, and radiotherapy, glioblastoma (GBM) remains an incurable and devastating brain cancer with a median survival of approximately 15 months following diagnosis. The efficacy of oncolytic virotherapy is a promising treatment for GBM but one important impediment is its rapid (and thus deleterious) clearance by host natural killer (NK) cells. In this application, we will investigate a novel pathway of NK cell killing of target cells, i.e., tumor cells and oncolytic virus-infected tumor cells and modulate this signaling pathway to improve the efficacy of oncolytic virotherapy for GBM.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI129582-08
Application #
9949624
Study Section
Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
Program Officer
Lapham, Cheryl K
Project Start
2017-07-18
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
8
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Ren, Yulin; Gallucci, Judith C; Li, Xinxin et al. (2018) Crystal Structures and Human Leukemia Cell Apoptosis Inducible Activities of Parthenolide Analogues Isolated from Piptocoma rufescens. J Nat Prod 81:554-561
Wu, Xiaojin; Xie, Yiyu; Wang, Chang et al. (2018) Prediction of acute GVHD and relapse by metabolic biomarkers after allogeneic hematopoietic stem cell transplantation. JCI Insight 3:
Tang, Xiaowen; Yang, Lin; Li, Zheng et al. (2018) First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. Am J Cancer Res 8:1083-1089
Wang, Hongwei; Zhang, Yibo; Wu, Xiaojin et al. (2018) Regulation of Human Natural Killer Cell IFN-? Production by MicroRNA-146a via Targeting the NF-?B Signaling Pathway. Front Immunol 9:293
Pan, Pan; Huang, Yi-Wen; Oshima, Kiyoko et al. (2018) Could Aspirin and Diets High in Fiber Act Synergistically to Reduce the Risk of Colon Cancer in Humans? Int J Mol Sci 19:
Wang, Yufeng; Zhang, Yibo; Hughes, Tiffany et al. (2018) Fratricide of NK Cells in Daratumumab Therapy for Multiple Myeloma Overcome by Ex Vivo-Expanded Autologous NK Cells. Clin Cancer Res 24:4006-4017
Pan, Pan; Oshima, Kiyoko; Huang, Yi-Wen et al. (2018) Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors. Int J Cancer 143:886-896
Zhang, Xinfu; Zhang, Chengxiang; Yang, Xiaomei et al. (2018) Design, synthesis and evaluation of anti-CD38 antibody drug conjugate based on Daratumumab and maytansinoid. Bioorg Med Chem :
Wang, Yufeng; Dong, Wenjuan; Zhang, Yibo et al. (2018) Dependence of innate lymphoid cell 1 development on NKp46. PLoS Biol 16:e2004867
Victor, Aaron R; Weigel, Christoph; Scoville, Steven D et al. (2018) Epigenetic and Posttranscriptional Regulation of CD16 Expression during Human NK Cell Development. J Immunol 200:565-572

Showing the most recent 10 out of 16 publications