Department of Microbiology and Immunology
Jennifer Wu, PhD
1996-200 PhD, University of British Columbia, Vancouver, Canada
2000-2002 Postdoctoral Fellow, Fred Hutchinson Cancer Research Center
Office - HCC HO-612B
Lab - HCC HO-610
Research in my laboratory is focused on the molecular and cellular regulation of host immunity and inflammatory responses in tumor microenvironment by tumor secretive soluble elements, with emphasis on tumor shed proteins and secretive cytokines. One of mechanisms conveying tumor immune surveillance in cancer patients is though induced expression of the membrane-bound MHC I chain related molecules A and B (MICA and MICB) on tumor cell surface. These molecules serve as ligands for the immune activating receptor NKG2D to signal the activation of NK and CD8 T cell anti-tumor responses. In cancer patients with advanced diseases, cancer cells shed the membrane-bound MICA and MICB to produce immune suppressive soluble forms of sMICA and sMICB. Our recent study have shown that membrane-bound NKG2D ligand stimulates anti-tumor immunity whereas tumor shedding-derived soluble NKG2D ligands poses multiple detrimental effect to the host immune responses (Fig 1). These negative effects include perturbing NK cell homeostasis, driving expansion of MDSCs, skewing macrophage differentiation into alternatively activated phenotypes. The mechanistic understandings have endorsed soluble NKG2D ligand to be a valid cancer therapeutic target. Our very recent development has proven this concept and demonstrated that antibody targeting soluble NKG2D ligand sMIC refuels and revamps endogenous innate and adaptive immune responses. Our current research focuses are: 1) to investigate how NKG2D ligands may shift the balance of anti-tumor immunity and pro-tumorigenic inflammation through the NKG2D receptor mediated cross-talks among immune/inflammatory cell types using the transgenic animal models established in my laboratory; 2) to harness NKG2D-mediated tumor immunity to enhance current FDA approved cancer immunotherapy; 3) to understand and harness NKG2D pathway for various autoimmune disorders. Our laboratory has developed unique transgenic animal models and a bank of functional antibodies for these studies.
The other interested area in my research is to investigate how the inflammation may play a role in tumor initiation and progression using prostate as a model organism. With specific focus on the pleiotropic cytokine IL-6, we would like to address: 1) a fundamental question and mechanisms of inflammation and cancer risk; 2) the interplay of inflammation, metabolic disorder, and malignancy. We have established a serial of IL-6 expressing tumor cell lines and tissue-specific IL-6 transgenic animals to address these questions.
Recent Publications | Additional Publications
Liu G, Xiao G, Zhang J, Frey L, and Wu JD. (2017) Prostate-specific IL-6 transgene amplifies inflammation in the prostate and peri-prostatic adipose tissue and autonomously induces prostate neoplasm. Journal of Hematology and Oncology, in press.
Wallace K, DeToma A, Lewin DN, Sun S, Rockey D, Britten C, Wu JD, Alberg AJ, and Hill EG. (2017) Racial differences in colorectal cancer survival in younger and older patients: An analysis of the SEER data. Clinical Colorectal Cancer doi: 10.1016/j.clcc.2016.11.006.
Metelli A, Wu B, Fugle C, Rachidi S, Sun S, Zhang Y, Wu JD, Tomlinson S, Howe PH, Yang Y, Garrett-Mayer E, Liu B, and Li Z. (2016) Surface expression of TGF-beta docking receptor GARP promotes oncogenesis and immune tolerance in breast cancer. Cancer Research 76(24):7106-7117. PMID: 27913437
Liu Q, Li A, Tian Y, Wu JD, Liu Y, Li T, Chen Y, Han X, and Wu K. (2016) The CXCL8-CXCR1/2 pathways in cancer. Cytokine Growth Factor Rev 31:61-71. Review. PMID: 27578214
Liu Q, Li A, Tian Y, Liu Y, Li T, Zhang C, Wu JD, Han X, Wu K. (2016) The expression profile and clinic significance of the SIX family in non-small cell lung cancer. J Hematol Oncol 9(1):119.
Basher F, Lu S, Wong H, and Wu JD. (2015) Cooperative anti-tumor effect of soluble MIC neutralizing monoclonal antibody and IL-15 agonists ALT-803 in preclinical animal models. OncoTarget 7(1):814:830.
Wu JD. (2015) Antibody targeting soluble NKG2D ligand sMIC refuels and invigorates the endogenous immune system to fight cancer. OncoImmunology Commentary 5(3):e1095434.
Lu S, Zhang J, Liu D, Li G, Staveley-O'Carroll KF, Li Z, and Wu JD. (2015) Non-blocking monoclonal antibody targeting soluble MIC revamps endogenous innate and adaptive anti-tumor responses and eliminates primary and metastatic tumors. Clin Cancer Res 21(21):4819-30. PMCID: 4631684
Xiao G, Wang X, Sheng J, Lu S, Yu X, and Wu JD. (2015) Soluble NKG2D ligand promotes MDSC expansion and skews macrophage to the alternatively activated phenotype. Journal of Hematology & Oncology 8:13-23. PMCID: 25887583
Zhang J, Basher F, and Wu JD. (2015) NKG2D ligands in tumor immunity: Two sides of a coin (Review). Front Immunol 6:97-104.
Wu JD. (2014) NKG2D ligands in cancer immunotherapy: Target or not? Austin Journal Of Clinical Immunology 1(1):2-3. PMC4257473
Wu JD and Yu E. (2014) Insulin-like growth factor receptor-1 (IGF-IR) as a target for prostate cancer therapy (Review). Cancer and Metastasis 33(2-3):607-17. PMID 24414227
Morales C, Rachidi S, Fenghong, Sun S, Ouyang X, Garrett-Mayer E, Wu JD, Liu B, and Li Z. (2014) Immune chaperone gp96 drives the contributions of macrophages to inflammatory colon tumorigenesis. Cancer Research PMID 24322981
Wu JD. (2013) IL-15 agonists: The cancer cure cytokine. J Genetic and Molecular Medicine 7:85. PMC3938108
Liu G, Lu S, Wang X, Page ST, Greenberg NM, Higano C, Plymate SR, Sun S, Li Z, and Wu JD. (2013) Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis. J Clin Invest 123(10):4410-22. PMC3784540
Florczyk SJ, Liu G, Kievit FM, Wu J, and Zhang M. (2012) 3D Porous chitosan-alginate scaffolds: new matrix for studying prostate cancer cell and lymphocyte interaction in vitro. Adv Healthc Mater 1(5):590-9.
Rojas A, Liu G, Colemen I, Nelson P, Fisher PB, Plymate SR, Zhang M, and Wu JD. (2011) IL-6 promotes prostate tumorigenesis and progression through autocrine cross-activation of IGF-IR. Oncogene 30:2345-55.
Page ST, Lin D, Mostaghel EA, Marck B, Wright J, Wu JD, Amory JK, Nelson PS, and Matsumoto AM. (2011) Dihydrotestosterone administration does not increase intraprostatic androgen concentrations or alter prostate androgen receptor action in healthy men: a randomized-controlled trial. J Clin Endocrinol Metab 96(2):430-7.
Leung M, Florczyk S, Kievit F, Veiseh O, Wu JD, Park J, and Zhang M. (2010) Three-dimensional porous chitosan-alginate scaffolds as an in vitro model for hepatocellular carcinoma tumor microenvironment. Pharm Res 27(9):1939-48.
Liu G, Atteridge CL, Lundgren AD, Wang X, and Wu JD. (2010) The membrane type matrix metalloproteinase MMP14 mediates shedding of MICA independent of ADAMs. J Immunology 184 (7):3346-50.
Wang X, Lundgren AD, Singh P, Goodlett DR, Plymate SR, Wu JD. (2009) A six-amino acid motif in the alpha3 domain of MICA is the cancer therapeutic target to inhibit shedding. Biochem Biophys Res Commun 87:476-81.
Sprenger CC, Haugk K, Sun S, Coleman I, Nelson PS, Vessella RL, Ludwig DL, Wu JD, and Plymate SR. (2009) Transforming growth factor-beta-stimulated clone-22 (TSC-22) is an androgen-regulated gene that enhances prostate cancer following insulin-like growth factor-1 reception inhibition. Clin Cancer Res 15:7634-7641.
Wu JD, Lin DW, Page ST, Atteridge KL, True LD, and Plymate SR. (2009) Oxidative DNA damage in the prostate may predispose men to a higher risk of prostate cancer. Translational Oncology 2:39-45.
Wu JD, Atteridge K, Wang XJ, Seya T, and Plymate SR. (2009) Obstructing shedding of the immune stimulatory MICB prevents tumor formation: Implication for targeted cancer therapy. Clin Can Res 15:632-40. 19147769
Plymate SR, Haugk K, Coleman I, Woodke L, Vessella R, Nelson P, Montgomery RB, Ludwig DL, and Wu JD. (2007) An antibody targeting the type I insulin-like growth factor receptor enhances the castration-induced response in androgen-dependent prostate cancer. Clin Cancer Res 13:6429-39.
Wu JD, Haugk K, Woodke L, Nelson P, Coleman I, and Plymate SR. (2006) Interaction of IGF signaling and the androgen receptor in prostate cancer progression (Review). JCB 99:392-401.
Page ST, Plymate SR, Bremner WJ, Hess DL, Matsumoto AM, Lin DL, and Wu JD. (2006) Effect of medical castration and testosterone replacement on CD4+ CD25+ T cells, CD8+ T cell IFNg expression, and NK cells: A physiological role for testosterone and/or its metabolites. Am J Physiol Endocrinol Metab 290:E856-E863.
Wu JD, Haugk K, Higgins LM, Vessella R, Montgomery RB, Ludwig DL, and Plymate SR. Combined in vivo effect of A12, a type 1 insulin-like growth factor antibody, and docetaxel against prostate cancer tumors. Clin Cancer Research 12:6153-60, 2006.
Wu JD, Odman A, Higgins L, Haugk K, Vessella R, Ludwig D, and Plymate SR. (2005) In vivo effects of the human type 1 insulin-like growth factor receptor antibody A12 on androgen-dependent and androgen-independent xenograft human prostate tumors. Clin Cancer Res 11:3065-73.
Wu JD. (2005) Counteracting MIC/NKG2D immunity by shedding in prostate cancer. Enhancer: Biotherapy of Cancer 3(2):18-9.
Wu JD, Higgins L, Steinle A, Cosman D, Haugk K, Plymate SR. (2004) Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer. J Clin Invest 114:560-568.
Wu JD, Haugk K, and Plymate SR. (2003) Activation of pro-apoptotic MAPK pathway in the prostate cancer cell line M12 expressing a truncated IGF-IR. Hormone and Metab Res 35:751-757.
Wu JD, Chalupny NJ, Manley TJ, Riddell SR, Cosman D, and Spies T. (2003) Intracellular retention of the MHC class I-related chain B ligand of NKG2D by the human CMV UL16 glycoprotein. J Immunol 170:4196-4200.
Groh V, Wu JD, Yee C, and Spies T. (2002) Tumor-derived soluable MIC ligands impair expression of NKG2D and T cell activation. Nature 419:734-738.
Wu JD, Spies V, and Spies T. (2002) T cell antigen receptor engagement and specificity in the recognition of stress-induced MIC by human epithelial gamma-delta T cells. J Immunol 169(3):1236 –1240.
Current Research Support
R01 CA204021 (PI: Wu)
NIH/NCI 7/1/2016 – 6/30/3021 $228,000 direct/yr (renewal of 7R01 CA149405)
Target MIC shedding to revive anti-tumor immunity.
The major goal is to delineate the mechanisms by which sMIC impairs NK homeostasis.
R01CA208246-01 (PI: Wu)
NIH/NCI 9/1/2016 – 8/30/2021 $228,000 direct/yr NKG2D
Superagonist Co-Stimulation to enhance adaptive immunotherapy of cancer.
The goal is delineated the super-costimulatory nature of sMIC/anti-MIC antibody complex in stimulating antigen- specific CD8 T cell responses.
1 U54 MD010706-01 (MPI: Halbert as lead PI)
NIH/NCI 9/1/16 – 8/30/2021 Total requested $6,716,090. Project 2 requested $233,000/direct per year.
Medical University of South Carolina Transdisciplinary Collaborative Center in Precision Medicine and Minority Men's Health
Role: Co-Leader of Project 2
Idea Development Award W81XWH-15-1-0406 (PI: Wu)
DOD-USARMC (PCRP) 7/1/2015- 6/30/2018 Total direct $375,000
Co-targeting CTLA4 and soluble NKG2D ligand for Metastatic Prostate Cancer.
HCC Pilot Award (PI: K. Wallace; Co-PI: J. Wu)
5/1/2016 – 4/30/2017 Total $100,000
Race, Pathomolecular Signature and Colorectal Cancer Survival
1R41CA206688-A1 (PI: Wu)
NIH/NCI 9/1/16 – 8/31/17 SubAward from CanCure LLC Total $89,999
Optimizing an immune stimulatory therapeutic antibody for human use.
The goal is to optimize the anti-MIC antibody biochemically or biophysically for clinical application.
Completed Research Support (Last 3 years)
7R01 CA149405 (PI: Wu)
NIH/ NCI 07/01/2010-07/30/2016 Total direct $1,165,000
Inhibiting MIC shedding to revive host NKG2D tumor immunity in cancer progression.
David A Mazzone Challenge Award (PI: Wu)
Prostate Cancer Foundation 9/1/2013 – 8/30/2015 Total direct $500,000
Synergistic immune/metabolism therapy for metastatic prostate cancer.
The major goal is to test combinatory therapy of inhibiting MIC shedding with inhibitors of cancer cell lipid metabolism for prostate cancer.
Innate Pharma Sponsored Research (PI: Wu)
4/1/2015 – 9/30/2016 Total direct $235,438
Pre-clinical validation of anti-MIC therapy.