Identification of both MHC class I and II restricted antigens has provided opportunities to develop more effective cancer vaccines, however, current immunotherapy strategies with tumor antigens are relatively ineffective and have not produced compelling evidence of any durable therapeutic benefits. Recent studies suggest that inflammatory Th17 cells and innate immunity at tumor sites may promote rather than inhibit cancer development and progression. Moreover, CD4+ regulatory T (Treg) cells at tumor sites potently suppress the CD4+ and CD8+ T-cell responses elicited by vaccination, thus promoting tumor growth. These studies suggest that understanding of the interplay between immune cells and tumor cells is a critical step to develop more effective cancer therapy. The underlying rationale is that inflammation is a major driving force in the pathogenesis of many types of cancer, including colorectal cancer and viral infection-associated malignancies. The delicate and dynamic balance among antitumor immunity, inflammatory CD4+ Th17 cells and immune suppressive cells may be important factor in tumor elimination, development and progression. Despite the importance of inflammatory cytokines and CD4+ Th17 cells in cancer, their role and regulatory mechanisms in cancer remain controversial. We therefore hypothesize that innate immune signaling is critical in the control of inflammation, which in turn modulates adaptive immunity and CD4+ Th17 cell differentiation. Thus, identification of key innate immune signaling molecules that control inflammation and Th17 differentiation will be critical for us to define the role of inflammation and Th17 cells in inflammation-associated cancer development and to dissect molecular mechanisms by which inflammatory cytokines and Th17 cells directly or indirectly modulate tumor development. To test our central hypothesis, we propose three aims: 1) To determine whether NLRC5 and TAK1 can modulate key proinflammatory cytokines and Th17 cells in vivo;2) To define the function of inflammatory cytokines and Th17 cells in cancer development;3) To enhance antitumor immunity by manipulating innate signaling molecules, Th17 and Treg cells. A favorable outcome would open new opportunities for treating cancer and other immune diseases through regulating these inflammation and subsets of CD4+ T cells.

Public Health Relevance

Immunotherapy is a promising treatment for cancer patients, but current strategies are relatively ineffective, mainly due to incomplete understanding of knowledge of the interplay between immune cells and tumor cells. The goal of this project is to understand the role and mechanisms of inflammation and Th17 cells in the tumor microenvironment, which aids in developing more effective strategies for cancer immunotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA101795-08
Application #
8519948
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2003-07-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
8
Fiscal Year
2013
Total Cost
$255,710
Indirect Cost
$91,266
Name
Methodist Hospital Research Institute
Department
Type
DUNS #
185641052
City
Houston
State
TX
Country
United States
Zip Code
77030
Qin, Yunfei; Liu, Qingxiang; Tian, Shuo et al. (2016) TRIM9 short isoform preferentially promotes DNA and RNA virus-induced production of type I interferon by recruiting GSK3β to TBK1. Cell Res 26:613-28
Ning, Bo; Li, Wenyuan; Zhao, Wei et al. (2016) Targeting epigenetic regulations in cancer. Acta Biochim Biophys Sin (Shanghai) 48:97-109
Jin, Shouheng; Tian, Shuo; Chen, Yamei et al. (2016) USP19 modulates autophagy and antiviral immune responses by deubiquitinating Beclin-1. EMBO J 35:866-80
Yang, Zhifen; Xian, Huifang; Hu, Jiajia et al. (2015) USP18 negatively regulates NF-κB signaling by targeting TAK1 and NEMO for deubiquitination through distinct mechanisms. Sci Rep 5:12738
Burchfield, Jana S; Li, Qingtian; Wang, Helen Y et al. (2015) JMJD3 as an epigenetic regulator in development and disease. Int J Biochem Cell Biol 67:148-57
Wu, Jian; Cai, Baowei; Sun, Wenxiang et al. (2015) Genome-wide Analysis of Host-Plasmodium yoelii Interactions Reveals Regulators of the Type I Interferon Response. Cell Rep 12:661-72
Cui, Jun; Song, Yanxia; Li, Yinyin et al. (2014) USP3 inhibits type I interferon signaling by deubiquitinating RIG-I-like receptors. Cell Res 24:400-16
Wang, Mingjun; Yin, Bingnan; Wang, Helen Y et al. (2014) Current advances in T-cell-based cancer immunotherapy. Immunotherapy 6:1265-78
Cui, Jun; Chen, Yongjun; Wang, Helen Y et al. (2014) Mechanisms and pathways of innate immune activation and regulation in health and cancer. Hum Vaccin Immunother 10:3270-85
Sonpavde, Guru; Wang, Mingjun; Peterson, Leif E et al. (2014) HLA-restricted NY-ESO-1 peptide immunotherapy for metastatic castration resistant prostate cancer. Invest New Drugs 32:235-42

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