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.
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.
|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|
|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|
|Wu, Jian; Tian, Linjie; Yu, Xiao et al. (2014) Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality. Proc Natl Acad Sci U S A 111:E511-20|
|Li, Qingtian; Zou, Jia; Wang, Mingjun et al. (2014) Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation. Nat Commun 5:5780|
|Deng, Tuo; Lyon, Christopher J; Minze, Laurie J et al. (2013) Class II major histocompatibility complex plays an essential role in obesity-induced adipose inflammation. Cell Metab 17:411-22|
|Zhao, Wei; Li, Qingtian; Ayers, Stephen et al. (2013) Jmjd3 inhibits reprogramming by upregulating expression of INK4a/Arf and targeting PHF20 for ubiquitination. Cell 152:1037-50|
|Ajibade, Adebusola A; Wang, Helen Y; Wang, Rong-Fu (2013) Cell type-specific function of TAK1 in innate immune signaling. Trends Immunol 34:307-16|
|Tong, Yanzheng; Cui, Jun; Li, Qingtian et al. (2012) Enhanced TLR-induced NF-ýýB signaling and type I interferon responses in NLRC5 deficient mice. Cell Res 22:822-35|
|Wang, Helen Y; Wang, Rong-Fu (2012) Enhancing cancer immunotherapy by intracellular delivery of cell-penetrating peptides and stimulation of pattern-recognition receptor signaling. Adv Immunol 114:151-76|
|Cui, Jun; Li, Yinyin; Zhu, Liang et al. (2012) NLRP4 negatively regulates type I interferon signaling by targeting the kinase TBK1 for degradation via the ubiquitin ligase DTX4. Nat Immunol 13:387-95|
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