Tumor tissues gradually form immune barriers that trap antigens and prevent adequate antigen presentation in draining lymph node and prevent CTL expanding and attacking tumor. Furthermore, the local tumor environment induces regulatory T cells that suppress incoming CD8+ cells. The expression of a newly identified TNFSF member, LIGHT, within the tumor induced lymphoid-like structures in the cancerous tissue resulting in tumor rejection at local and distal sites. However, the mechanisms of how LIGHT provoke such strong anti-tumor immunity and whether targeting local tumors with LIGHT can be effective for treating spontaneous metastasis have not been well studied. Our preliminary data suggest that LIGHT not only can attract and stimulate tumor-specific CDS* T cells, but also regulate NK and CD4* suppressive cells, which contribute positively and negatively to tumor rejection, respectively. It is hypothesized that locally targeted tumor with LIGHT induces strong anti-tumor immunity inside tumor through multiple regulation pathways affecting NK, CD4+, CD8+, and stromal cells. We plan to investigate whether and how tumor microenvironments induce immune tolerance and develop new immunotherapies for treating metastatic cancer. Our goal is to explore whether tumor suppressive microenvironment can be effectively altered to generate enough CTL to eradicate distal tumor. Specifically, we will elucidate the mechanisms for LIGHT-mediated tumor rejection and key players inside tumor that regulate positively or negatively CTL.
In aim 1, we will develop new approaches to eradicate metastasis by targeting primary tumors with locally delivered LIGHT.
In aim 2, we will investigate how LIGHT activates NK cells for tumor rejection.
In aim 3, we will determine whether LIGHT can reverse regulatory T cell-mediated suppression within the tumor microenvironment. Therefore, this study will further define the molecular mechanisms for tumor-induced immune evasion and the role of LIGHT on key cellular components inside tumor microenvironment for turner rejection. Furthermore, this study will develop clinically relevant approaches to treating an established cancer and metastatic tumors Lay Language: This study will help us to understand how local treatment of tumors can lead to the rejection of distal tumors and develop possible new immunotherapies for cancers, infectious diseases, and autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA115540-04
Application #
7572974
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Howcroft, Thomas K
Project Start
2006-04-01
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
4
Fiscal Year
2009
Total Cost
$383,381
Indirect Cost
Name
University of Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Zhu, Gui-Dong; Fu, Yang-Xin (2013) [Design of next generation antibody drug conjugates]. Yao Xue Xue Bao 48:1053-70
Burnette, Byron C; Liang, Hua; Lee, Youjin et al. (2011) The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res 71:2488-96
Tumanov, Alexei V; Koroleva, Ekaterina P; Guo, Xiaohuan et al. (2011) Lymphotoxin controls the IL-22 protection pathway in gut innate lymphoid cells during mucosal pathogen challenge. Cell Host Microbe 10:44-53
Washburn, Michael L; Kovalev, Grigoriy I; Koroleva, Ekaterina et al. (2010) LIGHT induces distinct signals to clear an AAV-expressed persistent antigen in the mouse liver and to induce liver inflammation. PLoS One 5:e10585
Wang, Yugang; Zhu, Mingzhao; Yu, Ping et al. (2010) Promoting immune responses by LIGHT in the face of abundant regulatory T cell inhibition. J Immunol 184:1589-95
Wang, Yugang; Koroleva, Ekaterina P; Kruglov, Andrei A et al. (2010) Lymphotoxin beta receptor signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection. Immunity 32:403-13
Park, SaeGwang; Jiang, Zhujun; Mortenson, Eric D et al. (2010) The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell 18:160-70
Tumanov, Alexei V; Koroleva, Ekaterina P; Christiansen, Peter A et al. (2009) T cell-derived lymphotoxin regulates liver regeneration. Gastroenterology 136:694-704.e4
Miller, Mendy L; Sun, Yonglian; Fu, Yang-Xin (2009) Cutting edge: B and T lymphocyte attenuator signaling on NKT cells inhibits cytokine release and tissue injury in early immune responses. J Immunol 183:32-6
Sun, Yonglian; Brown, Nicholas K; Ruddy, Matthew J et al. (2009) B and T lymphocyte attenuator tempers early infection immunity. J Immunol 183:1946-51

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