Laboratory of Xiang-Yang (Shawn) Wang, Ph.D.
The overall research focus of the lab is studying stress response and its key players (e.g., stress proteins or chaperone molecules), “danger”-sensing pattern recognition molecules (e.g., scavenger receptors) in inflammation, immunity and host response. In addition to elucidating their biological functions and mechanisms of their action, this group is also interested in developing novel therapeutic approaches for the treatment of cancer and other diseases.
- Molecular chaperoning and cancer immunotherapy
Large stress/heat shock proteins, called hsp110 and grp170, serve as molecular chaperones in numerous cellular processes that maintain protein homeostasis under both physiological and stress conditions. Based on their exceptional capacity in shuttling and cross-presenting exogenous antigens, researchers in Dr. Wang’s lab have developed and evaluated several chaperone-based immunotherapies, including a recombinant chaperone complex vaccine targeting defined tumor antigens. Ongoing studies are aimed to address the mechanisms of large stress protein-facilitated antigen recognition, processing, and presentation by specialized antigen-presenting cells, such as dendritic cells. In addition to protein antigen/substrate, large stress protein interactions with pathogen-associated molecules and resultant immune outcomes are under investigation. Current work in the laboratory also involves development of modified chaperone-based immune modulating agent to enhance vaccine potency or promote tumor response to other therapeutics.
- Scavenger receptors in host immunity and diseases
Scavenger receptors (SRs) act as stress “sensors” and recognize conserved patterns unique to microorganisms and self (e.g., modified macromolecules). Dr. Wang’s team made the first discovery that SRA/CD204, a prototype member of the SR family, attenuates therapeutically induced antitumor immunity. Researchers are investigating the mechanisms by which SRA/CD204 regulates an adaptive immune response and immune recognition of tumors using molecular, cellular and immunological approaches. Ongoing studies also aim to develop novel SRA/CD204-targeted approaches (molecular/immunologic/pharmacologic) to improve the efficacy of immunotherapy.
SRs function as pattern recognition receptors (PRRs) and are expressed primarily on myeloid cells (e.g., dendritic cell and macrophage) that are known to play crucial roles in regulation of an inflammatory response and tissue homeostasis. This group is interested in understanding the functions of these molecules under environmental, physiological, and pathological stress conditions, including heat shock, oxidative stress, radiation, viral infection, chronic inflammatory diseases, or autoimmune disorders.
Novel cancer therapeutic strategies engaging multiple antitumor mechanisms
Cancer is generally considered to be a highly heterogeneous disease. Multi-functional strategies are mandatory to overcome tumor resistance and to achieve improved antitumor efficacy. The researchers are testing rationally combined therapeutic approaches that can selectively target cancer cells for destruction and concurrently promote ”immunogenic“ cancer cell death to generate protective antitumor immunity. It would lead to more effective control of cancer metastases and prevention of tumor recurrence. Current research also includes understanding of tumor-induced immune tolerance or suppression mechanisms, immune cell-tumor interaction in the tumor microenvironment, as well as their potential impact on cancer treatments.
Chunqing Guo, Ph.D.
Xia Li, Ph.D.
Zheng Liu, Ph.D.
Yu X, Guo C, Yi H, Qian J, Fisher PB, Subjeck JR, and Wang XY. A multifunctional chimeric chaperone serves as a novel immune modulator inducing therapeutic antitumor immunity. Cancer Research 2013, 73 (7): 2093-2103.
Guo C, Manjili MH, Subjeck JR, Sarkar D, Fisher PB, and Wang XY. Therapeutic cancer vaccines: past, present and future. Adv. Cancer Research 2013, 119: 421-475.
Zuo D, Yu X, Guo C, Wang H, Qian J, Yi H, Lu X, Lv Z-P, Subjeck JR, Zhou H, Sanyal AJ, Chen Z, and Wang XY. Scavenger receptor SRA restrains T cell activation and protects against concanavalin A-induced hepatic injury. Hepatology 2013, 57(1): 228-238.
Yi H, Guo C, Yu X, Zuo D, Wang XY. Mouse CD11b+Gr-1+ myeloid cells can promote T helper 17 cell differentiation and experimental autoimmune encephalomyelitis. Journal of Immunology 2012, 189(9):4295-304.
Guo C, Yi H, Yu X, Zuo D, Qian J, Yang G, Foster BA, Subjeck JR, Sun X, Mikkelson RB, Fisher PB, Wang XY. In situ vaccination with CD204 gene-silenced dendritic cell, not unmodified dendritic cell, enhances radiation therapy of prostate cancer. Molecular Cancer Therapeutics 2012, 11(11): 2331-2341.
Zuo D, Yu X, Yi H, Guo C, Chen X, Conrad DH, Guo TL, Chen Z, Fisher PB, Subjeck JR, and Wang XY. Molecular chaperoning by glucose-regulated protein 170 in the extracellular milieu promotes macrophage-mediated pathogen sensing and innate immunity. FASEB Journal 2012, 26(4):1493-1505.
Yi H, Guo CQ, Yu X, Gao P, Qian J, Zuo D, Manjili MH, Fisher PB, Subjeck JR and Wang XY. Targeting the immunoregulator SRA/CD204 potentiates specific dendritic cell vaccine-induced T cell responses and antitumor immunity. Cancer Research 2011, 71(21):6611-6620.
Qian J, Yi H, Baek SH, Guo CQ, Yu X, Zuo DM, Chen X, Kane J, Repasky EA, Subjeck JR and Wang XY. CD204 suppresses large heat shock protein-facilitated priming of tumor antigen gp100-specific T-cells and chaperone vaccine activity against mouse melanoma. Journal of Immunology 2011, 187(6):2905-2914.
Yu X, Yi H, Guo C, Wang Y, Kim H, Subjeck JR, and Wang XY. Pattern recognition scavenger receptor A attenuate TLR4 induced NF-kB activation by direct inference with TRAF-6 ubiquitination. Journal of Biological Chemistry 2011, 286(21):18795-18806.
Hu F, Yu X, Wang HX, Yi H, Zuo D, Guo C, Tirosh B, Subjeck JR, Qiu X and Wang XY. ER stress and its regulator X-box binding protein 1 enhance polyIC induced inflammatory response in dendritic cells. European Journal of Immunology 2011, 41:1086–1097.
Wang XY, Chen X, Facciponte J, Repasky ER, Kane J, and Subjeck JR. Superior antitumor response induced by large stress protein chaperoned protein antigen compared with peptide antigen. Journal of Immunology 2010, 184:6309-6319.
Yi H, Yu X, Gao P, Wang Y, Kim H, Subjeck JR, and Wang XY. Pattern recognition scavenger receptor SRA/CD204 down-regulates toll-like receptor 4 (TLR4) signaling-induced CD8 T-cell activation. Blood 2009, 113:5819-5828.
Gao P, Sun X, Chen X, Foster BA, Subjeck JR, Fisher PB, and Wang XY. Secretable chaperone grp170 enhances therapeutic activity of a novel tumor suppressor Mda-7/IL-24. Cancer Research 2008, 68:3890-3898.
Wang XY, Facciponte JG, Chen X, Subjeck JR, and Repasky EA. Scavenger receptor-A negatively regulates tumor immunity. Cancer Research 2007, 67:4996-5002.