Cancer ranks as the second leading cause of death, contributing to nearly 1 in every 4 death in the US. Current cancer immunotherapies, especially checkpoint blockade, is largely influenced by PD-L1 expression in tumors; and patients with limited PD-L1 positive expression are normally less responsive to the immunotherapy. These findings suggest new technologies are needed to for PD-L1 resistant tumors. Cyclic [G(3',5')pA(3',5')p] (cGAMP) has recently emerged as an exciting new class of vaccine adjuvants, which sequentially activate innate immune responses and orchestrate adaptive immunity. Tumor associated macrophages (TAMs), a major type of immune cells in tumor microenvironment, are a potent target for adjuvant therapy. Particulate systems are ideal vehicles for targeting TAM population within tumor. Additionally, combination therapy holds great promise for tumor prevention and treatment. Most important, the critical role of cancer microbiome is gaining increased interests for cancer therapy. We hypothesize that Particulate cGAMP adjuvants targeting TAMs can enhance anti-tumor immune response and reverse the pro-tumorigenic microenvironment in both PD-L1 responsive and resistant cancers, and improve the anti-tumor efficiency in combination with checkpoint blockade and tumor resection. We have tested and will continue to test the hypothesis using B16F10 melanoma (subcutaneous and lung metastasis models; PD-L1 responsive) and C3(1)Tag basal-like breast cancer (orthotopic and spontaneous GEM models; PD-L1 resistant), and test the following specific aims:
Aim 1. Particulate delivery of STING agonist as anti-cancer immuotherapeutics: (F99 phase). We optimized liposomal NP and Ace-DEX MP delivery systems for cGAMP to evaluate the cellular uptake and M2->M1 skewing capacity, and detect major histocompatibility (MHC) gene and costimulatory gene expression and cytokine production in vitro. We also investigated the tissue distribution of particulate cGAMPs and their anti-tumor efficacy in above-mentioned tumor models.
Aim 2. Mechanism by which particulate delivery of STING agonist acts an as anti-cancer immuotherapeutic and combination therapies: (F99 phase). We will study the role of macrophage, CD4+ and CD8+ T cells, and NK cells in anti-tumor response of particulate cGAMPs. We will also monitor long term survival and tumor recurrence by combination therapies of particulate cGAMPs with anti-PD-L1 antibodies and tumor resection in above- mentioned tumor models.
Aim 3. The Postdoctoral Research Direction (K00 phase). I will pursue my interest in understanding the mechanism and functional role of gut microbiota in host response to cancer development and therapy, meanwhile, with a particular interest in studying the role of oral microbiota in response to head and neck cancer therapeutics and restoration.

Public Health Relevance

This project is focused on studying cancer immunotherapy through the application of nanotechnology and investigating the role of cancer microbiome. The overall research goal is to seek treatment regimens of difficult cancers that have little treatment options and prevent of their relapse.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Project #
5F99CA223019-02
Application #
9566147
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Mcguirl, Michele
Project Start
2017-09-18
Project End
2019-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Cheng, Ning; Watkins-Schulz, Rebekah; Junkins, Robert D et al. (2018) A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1-insensitive models of triple-negative breast cancer. JCI Insight 3:
Truax, Agnieszka D; Chen, Liang; Tam, Jason W et al. (2018) The Inhibitory Innate Immune Sensor NLRP12 Maintains a Threshold against Obesity by Regulating Gut Microbiota Homeostasis. Cell Host Microbe 24:364-378.e6
Junkins, Robert D; Gallovic, Matthew D; Johnson, Brandon M et al. (2018) A robust microparticle platform for a STING-targeted adjuvant that enhances both humoral and cellular immunity during vaccination. J Control Release 270:1-13
Kurkjian, Cathryn J; Guo, Hao; Montgomery, Nathan D et al. (2017) The Toll-Like Receptor 2/6 Agonist, FSL-1 Lipopeptide, Therapeutically Mitigates Acute Radiation Syndrome. Sci Rep 7:17355
Rotty, Jeremy D; Brighton, Hailey E; Craig, Stephanie L et al. (2017) Arp2/3 Complex Is Required for Macrophage Integrin Functions but Is Dispensable for FcR Phagocytosis and In Vivo Motility. Dev Cell 42:498-513.e6
Wu, Tao; Tan, Lei; Cheng, Ning et al. (2016) PNIPAAM modified mesoporous hydroxyapatite for sustained osteogenic drug release and promoting cell attachment. Mater Sci Eng C Mater Biol Appl 62:888-96
Wu, Tao; Cheng, Ning; Xu, Chun et al. (2016) The effect of mesoporous bioglass on osteogenesis and adipogenesis of osteoporotic BMSCs. J Biomed Mater Res A 104:3004-3014
Yan, Qi; Li, Yuhong; Cheng, Ning et al. (2015) Effect of retinoic acid on the function of lipopolysaccharide-stimulated bone marrow stromal cells grown on titanium surfaces. Inflamm Res 64:63-70
Dai, Jing; Cheng, Ning; Miron, Richard J et al. (2014) Effect of decreased implant healing time on bone (re)modeling adjacent to plateaued implants under functional loading in a dog model. Clin Oral Investig 18:77-86
Cheng, Ning; Wang, Yuanqin; Zhang, Yufeng et al. (2013) The osteogenic potential of mesoporous bioglasses/silk and non-mesoporous bioglasses/silk scaffolds in ovariectomized rats: in vitro and in vivo evaluation. PLoS One 8:e81014

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