Yang-Xin Fu, M.D., Ph.D.

 

APPOINTMENTS

  • Professor, Department of Pathology, Committee on Immunology, Committee on Cancer Biology, Committee on Molecular Medicine/MPMM

EDUCATION

Ph.D., University of Miami, 1990

M.D., Shanghai Medical University, 1983

CONTACT INFORMATION

The University of Chicago
JFK R114
924 East 57th Street 
Chicago, Illinois 60637

 yxfu@bsd.uchicago.edu

Phone:  (773) 702-0929

Website (Department of Medicine)

RESEARCH SUMMARY

      My clinical background and strong interest in basic immunobiology have led me to integrate basic research into more pathogenesis and treatment of diseases.  The basic research in my laboratory is focused on understanding the biological consequences arising from the interaction between core molecules of the TNF superfamily, lymphotoxin (LT or TNFSF1) and LIGHT (TNFSF14), on lymphocytes, and their receptor, LTbR, on stromal cells. This research has contributed substantially to the definition of the critical role these molecules play in the development and function of lymphoid tissues. Our recent studies have defined the roles of these molecules in infectious and tumor immunity in mouse models and human patients.  Our research includes four major themes.

Critical role for lymphotoxin in the development and function of primary, secondary, and tertiary lymphoid tissues

      The relative contributions of lymphoid tissues and non-lymphoid tissues to various immune responses had not been defined previously due to the lack of appropriate animal models and the complicated nature of the issues involved.  Our pioneering studies have revealed the essential role of LT and TNF for the development and maintenance of lymphoid tissues.  Using LT-deficient mice, or antibody or soluble receptor blockade, we generated unique mouse models that lack various sets of secondary lymphoid tissues to define the roles of these structures in various tissues for different types of immune responses.  We have been studying the development and maintenance of complex lymphoid architecture using these models; Lately, we are exploring novel LTbR-stimulated NFkB pathways shape the development and function of lymphoid tissues which are important for priming and tolerance. 

1. To explore the role of LT-controlled gut immunity in bacterial and autoimmune colitis through regulating microbiota. 

2. To define the role of ILC3 in regulating microbiota and immune responses.  We have generated various conditional KO mice that defective RORgt or related regulatory factors such as STAT3 and Id2.

3.  To study how lymphoid tissues are regulated at early and late phase.

Target tumor tissues to generate systemic immune responses

Lack of effective infiltration of immune cells and proper expression of co-stimulatory molecule prevent effective immune response against established tumor.  Our understanding of the role of LIGHT on the LTbR-mediated lymphoid microenvironment and on its another receptor, HVEM (a costimulatory receptor) has allowed us to study the role of lymphoid-like microenvironment in autoimmune diseases and develop new strategies to target tumor with LIGHT to attract immune cells by LTbR signaling and activate T cells by HVEM inside tumor tissues. Indeed, local expression of LIGHT inside tumors causes development of lymphoid-like structures within those tumors.  This allows the rapid recruitment of naïve and activated T cells into tumor sites and generates an effective anti-tumor response.  Our future studies will attempt to reveal the cellular and molecular mechanisms governing tumor evasion and barriers in tumor bearing host.  These basic studies will also guide us in the development of novel approaches to immunotherapy to break tumor barriers and tumor induced tolerance.

1.     To investigate the mechanisms by which antibody based immunotherapy.  We will explore the role of antibodies in induction of cytokines, stress molecules, and Fc receptor mediated cross-priming. Currently, we have targeted CD20, HER2/neu and EGFR.

2.     To investigate the mechanisms ablative radiation initiates DNA damage, stress induction for innate and adaptive immunity that control tumor.  We will explore cellular and molecular mechanisms that are essential at initiating RT-mediated immunity

3.     To investigate whether targeting tumors with a novel fusion protein, consisting of anti-tumor antibody genetically fused to various cytokines or danger signals can further amplify the ablative RT or anti-oncogenic antibody mediated immunity.   We are exploring new fusion proteins that can change tumor environment and break tolerance inside tumor tissues.

4.     To determine the effects of currently used chemotherapeutic agents on host immune responses

5.   To determine the effect of endogenous danger signaling on triggering innate and adaptive immunity against tumor

SELECTED PAPERS

Lo JC, Wang Y, Tumanov AV, Bamji M, Yao Z, Reardon, CA, Getz GS, and Fu YX. Lymphotoxin beta receptor-dependent control of lipid homeostasis..  Science 316:285-288, 2007. (see “LIGHT Hits the Liver” in Perspectives at the same issue of Science, highlight in Nature Review Immunology).

Krieg, C, Boyman, O, Fu, Y. X., Kaye, J. B and T lymphocyte attenuator regulates CD8+ T cell-intrinsic homeostasis and memory cell generation. Nat. Immunol. 8:162-71, 2007.

Zhang, B, Bowerman, N. A, Salama, J. K, Schmidt, H, Spiotto, M. T. Schietinger, A. Yu, P. Fu, Y. X. Weichselbaum, R. R. Rowley, D. A. Kranz, D. M. Schreiber, H.  Induced sensitization of tumor stroma leads to eradication of established cancer by T cells.  J. Exp. Med.  204:49-55, 2007.

Kim KD, Zhao J, Auh S, Du P,. Yang, X., Tang H, and Fu YX.  Adaptive immune cells temper initial innate responses.  Nature Med 13:1248-1252, 2007 (see commentary entitled “Not so fast: adaptive suppression of innate immunity” in Nature Medicine (13: 1142-1144, 2007)  and highlight entitled “T cells calm the storm” by Nature Review Immunogy.

Zhu M, and FuYX, Coordinating Development of Medullary Thymic Epithelial Cells, Immunity  29:388, 2008.

Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, Beckett M, Sharma R, Chin RK, Tu T, Weichselbaum RR, and Fu Y-X.  Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: Changing strategies for cancer treatment  Blood. 114(3):589-95, 2009.  PMID: 19349616

Wang Y, Koroleva EP, Kruglov AA, Kuprash DV, Nedospasov SA, Fu YX, Tumanov AV. (*co-corresponding author).  LTR signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection.  Immunity. 2010 Mar 26;32(3):403-13.

Chen L, Park SM, Tumanov AV, Hau A, Sawada K, Feig C, Turner JR, Fu YX, Romero IL, Lengyel E, Peter ME.  CD95 promotes tumour growth.  Nature. 465(7297):492-6, 2010

Park SG, Jiang Z, Mortenson ED, Deng Liufu, Radkevich-Brown, O, Yang X, Sattar1, Yang Wang H, Brown NK, Greene M, Liu Y, Tang J, Wang S, and Fu YX.  The Therapeutic Effect of Anti-HER2/neu Antibody Depends on Both Innate and Adaptive Immunity. Cancer Cell 18:160–170, 2010.

Zhu M, Fu YX. Deflating the lymph node. Immunity. 34(1):8-10, 2011.

Tumanov AV, Koroleva EP, Guo X, Wang Y, Kruglov A, Nedospasov S, Fu YX.  Lymphotoxin Controls the IL-22 Protection Pathway in Gut Innate Lymphoid Cells during Mucosal Pathogen Challenge. Cell Host Microbe. 10(1):44-53, 2011

Qiu J, Heller JJ, Guo X, Chen ZM, Fish K, Fu YX, Zhou L. The Aryl Hydrocarbon Receptor Regulates Gut Immunity through Modulation of Innate Lymphoid Cells.  Immunity. 36(1):92-104, 2012

Moseman EA, Iannacone M, Bosurgi L, Tonti E, Chevrier N, Tumanov A, Fu YX, Hacohen N, von Andrian UH.  B Cell Maintenance of Subcapsular Sinus Macrophages Protects against a Fatal Viral Infection Independent of Adaptive Immunity.  Immunity. 36(3):415-26, 2012.

Upadhyay V, Poroyko V, Kim TJ, Devkota S, Fu S, Liu D, Tumanov AV, Koroleva EP, Deng L, Nagler C, Chang EB, Tang H, Fu YX.  Lymphotoxin regulates commensal responses to enable diet-induced obesity Nature Immunology.  13(10):947-53, 2012 (preview by NI and comments by NRI).

Upadhyay V, Fu YX.  Lymphotoxin signalling in immune homeostasis and the control of microorganisms.  Nat Rev Immunol. 13(4):270-9, 2013.

Hu H, Brittain GC, Chang JH, Puebla-Osorio N, Jin J, Zal A, Xiao Y, Cheng X, Chang M, Fu YX, Zal T, Zhu C, Sun SC. OTUD7B controls non-canonical NF-κB activation through deubiquitination of TRAF3. Nature 494(7437):371-4., 2013.

Qiu J, Guo X, Chen ZM, He L, Sonnenberg GF, Artis D, Fu YX, Zhou L. Group 3 Innate Lymphoid Cells Inhibit T-Cell-Mediated Intestinal Inflammation through Aryl Hydrocarbon Receptor Signaling and Regulation of Microflora. Immunity. 39(2):386-99, 2013

Gajewski TF, Schreiber H, Fu YX.Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013 14(10):1014-22.

Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR & Fu YX. Radiation and anti-B7-H1 provide synergistic treatment effects in murine cancer.    J. Clin. Invest. 124(2):687-9, 2014.

Guo X  Qiu J, Tu T, Yang X, Deng L, Anders RA. Zhou L. Fu YX. Differential STAT3 signaling in innate lymphoid cells mediates host defense against mucosal infection.  Immunity, 2014.

Yang X, Zhang X, Fu ML, Weicheslbaum RR, Gajewski T, Guo Y, Wang Y, Fu YX. Targeting the tumor microenvironment with interferon bridges innate and adaptive immune responses, Cancer Cell. 25(1):37-4, 2014.