Immunology is the study of biological systems used to defend the body against microbial pathogen infection and fight cancer. Recognition of the invading pathogens and tumor antigens by the antigen-presenting cells APCs including dendritic cells (DC) will activate APCs and allow these APCs to initiate innate and adaptive immune responses against infection and cancer.   Dr. Xuetao Cao's major research interests are innate immunity and inflammation, tumor immunology and immunotherapy. His group has made contributions to the understanding of innate signaling in immunity and inflammation, identification of cell subsets and new molecules in dendritic cell (DC)-initiated immune response and cancer immunotherapy.

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His group has identified and functionally characterized 22 novel molecules from a human dendritic cell (DC) cDNA library since 1998, including HSP70L1, Siglec-10, Septin-10, Cyclin-L2, Nrdp1, Rab7b, hPEBP4 and hCaMKIIN. His group identified several subsets of immune cells with regulatory function, for example, his group found that splenic stroma can drive mature DC to further proliferate and differentiate into IalowCD11bhigh regulatory DC subset which can feedback inhibit immune response. This subset of regulatory DC can also drive generation of new regulatory immune cell subsets including immunosuppressive memory T cells (IL-4hiIL-10hiCD44hiCD62L-CCR7-) and regulatory B cells (IL-10hiCD19hiFcγIIbhi), forming feedback loop for the control of immune response. This led to the hypothesis that the stromal microenvironment physiologically controls immune homeostasis. His group identified miRNomesin DCand also discovered one long-noncoding RNA lnc-DC in human DC differentiation and proposed its new working mode by directly binding cytoplasmic signaling molecule STAT3, adding insight to the epigenetic regulation of immune cell differentiation and function. His group has identified important mediators and regulators of innate receptor TLR/RIG-I-triggered innate inflammatory response. For example, his group discovered E3 ligase Nrdp1/DRP from human DC cDNA library (1998) and then identified Nrdp1 as the enhancer of type I interferon production. They proposed that Siglec-G, mouse homolog of human Siglec-10 his lab independently cloned from human DC library, can selectively help RNA viruses escape innate immune response by promoting RIG-I degradation. His group showed that membrane MHC-I and intracellular MHC-II molecules can negatively and positively regulate TLR-triggered response. His group showed that Romboid domain-containing protein Rhbdd3 controls autoimmunity and TLR response by suppressing DC production of IL-6 via K27-linked NEMO ubiquitination. His group identified miRNomesin DC and reported several microRNAs as regulators of type I interferon production and function. In the area of translational research, his group screened and identified several candidates of biomarkers such as microRNA-199 in the predication of cancer patients' prognosis and responsiveness to immunotherapy, and also investigated new approaches to cancer immunotherapy in basic and clinic trial. For example, his group identified hepatic RIG-I as one useful biomarker and tumor suppressor to predict survival and interferon-α therapeutic response in hepatocellular carcinoma patients. His group headed and completed a randomized multi-center Phase II clinical trial of autologous DC-based chemoimmunotherapy of metastatic cancer patients, and exciting therapeutic efficacy has been achieved.

Selected Publications

1.  Shen Q, Zhang Q, Shi Y, Shi Q, Jiang Y, Gu Y, Li Z, Li X, Zhao K, Wang C, Li N, Cao X. Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation. Nature. 2018; 554(7690):123-127.

2.  Wang P, Xu J, Wang Y, Cao X. An interferon-independent lncRNA promotes viral replication by modulating cellular metabolism. Science. 2017; 358(6366):1051-105.

3.  Chen K, Liu J, Liu S, Xia M, Zhang X, Han D, Jiang Y, Wang C, Cao X. Methyltransferase SETD2-Mediated methylation of STAT1 is critical for interferon antiviral activity. Cell. 2017; 170(3):492-506.

4.  Liu S, Jiang M, Wang W, Liu W, Song X, Ma Z, Zhang S, Liu L, Liu Y, Cao X. Nuclear RNF2 inhibits interferon function by promoting K33-linked STAT1 disassociation from DNA. Nat Immunol. 2018; 19(1):41-52.

5.  Zheng Q, Hou J, Zhou Y, Li Z, Cao X. The RNA helicase DDX46 inhibits innate immunity by entrapping m(6)A-demethylated antiviral transcripts in the nucleus. Nat Immunol. 2017; 18(10):1094-1103.

6.   Ding Y, Guo Z, Liu Y, Li X, Zhang Q, Xu X, Gu Y, Zhang Y, Zhao D, Cao X. The lectin Siglec-G inhibits dendritic cell cross-presentation by impairing MHC class I-peptide complex formation. Nat Immunol. 2016; 17(10):1167-1175.

7.   Li X, Zhang Q, Ding Y, Liu Y, Zhao D, Zhao K, Shen Q, Liu X, Zhu X, Li N, Cheng Z, Fan G, Wang Q, Cao X. Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity. Nat Immunol. 2016; 17(7):806-815.

8.   Liu Y, Gu Y, Han Y, Zhang Q, Jiang Z, Zhang X, Huang B, Xu X, Zheng J, Cao X. Tumor Exosomal RNAs Promote Lung Pre-metastatic Niche Formation by Activating Alveolar Epithelial TLR3 to Recruit Neutrophils. Cancer Cell. 2016; 30(2):243-256.

9.   Zhang Q, Zhao K, Shen Q, Han Y, Gu Y, Li X, Zhao D, Liu Y, Wang C, Zhang X, Su X, Liu J, Ge W, Levine RL, Li N, Cao X. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature. 2015; 525(7569):389-393.

10.   Yang M, Chen T, Li X, Tang S, Wang C, Gu Y, Liu Y, Xu S, Li W, Zhang X, Wang J, Cao X. K33-linked polyubiquitination of Zap70 by E3 ligase Nrdp1 controls activation of CD8+ T cells. Nat Immunol. 2015; 16(12):1253-1262.

11.   Wang P, Xue Y, Han Y, Lin L, Wu C, Xu S, Jiang Z, Xu J, Liu Q, Cao X. The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation. Science. 2014; 344(6181):310-313.

12.   Liu J, Han C, Xie B, Wu Y, Liu S, Chen K, Xia M, Zhang Y, Song L, Li Z, Zhang T, Ma F, Wang Q, Wang J, Deng K, Zhuang Y, Wu X, Yu Y, Xu T, Cao X. Rhbdd3 controls autoimmunity by suppressing the production of IL-6 by dendritic cells via K27-linked ubiquitination of the regulator NEMO. Nat Immunol. 2014; 15(7):612-622.

13.   Hou J, Zhou Y, Zheng Y, Fan J, Zhou W, Ng IO, Sun H, Qin L, Qiu S, Lee JM, Lo CM, Man K, Yang Y, Yang Y, Yang Y, Zhang Q, Zhu X, Li N, Wang Z, Ding G, Zhuang SM, Zheng L, Luo X, Xie Y, Liang A, Wang Z, Zhang M, Xia Q, Liang T, Yu Y, Cao X. Hepatic RIG-I predicts survival and interferon-α therapeutic response in hepatocellular carcinoma. Cancer Cell. 2014; 25(1):49-63. (cover story)

14.    Chen T, Yang M, Yu Z, Tang S, Wang C, Zhu X, Guo J, Li N, Zhang W, Hou J, Liu H, Han C, Liu Q, Gu Y, Qian C, Wan T, Cui L, Zhu M, Zheng W, Cao X. Small GTPase RBJ Mediates Nuclear Entrapment of MEK1/MEK2 in Tumor Progression. Cancer Cell. 2014; 25(5):682-696. (cover story)

15.   Chen W, Han C, Xie B, Hu X, Yu Q, Shi L, Wang Q, Li D, Wang J, Zheng P, Liu Y, Cao X. Induction of Siglec-G by RNA viruses inhibits the innate immune response by promoting RIG-I degradation. Cell. 2013; 152(3):467-478.

16.   Xia M, Liu J, Wu X, Liu S, Li G, Han C, Song L, Li Z, Wang Q, Wang J, Xu T, Cao X. Histone Methyltransferase Ash1l Suppresses Interleukin-6 Production and Inflammatory Autoimmune Diseases by Inducing the Ubiquitin-Editing Enzyme A20. Immunity. 2013; 39(3): 470-481.

17.   Xu S, Liu X, Bao Y, Zhu X, Han C, Zhang P, Zhang X, Li W, Cao X. Constitutive MHC class I molecules negatively regulate TLR-triggered inflammatory responses via the Fps-SHP-2 pathway. Nat Immunol. 2012; 13(6):551-559.

18.  Liu X, Zhan Z, Li D, Xu L, Ma F, Zhang P, Yao H and Cao X. Intracellular MHC class II molecules promote TLR-triggered innate immune responses by maintaining activation of the kinase Btk. Nat Immunol. 2011; 12(5):416-424.

19.  Ma F, Xu S, Liu X, Zhang Q, Xu X, Liu M, Hua M, Li N, Yao H, Cao X. The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-γ. Nat Immunol. 2011; 12(9):861-869.

20.  Hou J, Lin L, Zhou W, Wang Z, Ding G, Dong Q, Qin L, Wu X, Zheng Y, Yang Y, Tian W, Zhang Q, Wang C, Zhang Q, Zhuang S, Zheng L, Liang A, Tao W, and Cao X. Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as a therapeutic target for hepatocellular carcinoma. Cancer Cell. 2011; 19(2):232-243.

21.  Yang P, An H, Liu X, Wen M, Zheng Y, Rui Y, Cao X. The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a beta-catenin-dependent pathway. Nat Immunol. 2010; 11(6):487-494.

22.  Han C, Jin J, Xu S, Liu H, Li N, Cao X. Integrin CD11b negatively regulates TLR-triggered inflammatory response by activating Syk and promoting MyD88 and TRIF degradation via cbl-b. Nat Immunol. 2010; 11(8):734-742.

23.  Wang C, Chen T, Zhang J, Yang M, Li N, Xu X, Cao X. The E3 ubiquitin ligase Nrdp1 preferentially promotes TLR-mediated type I interferon production. Nat Immunol. 2009; 10 (7):744-752.

24.  An H, Hou J, Zhou J, Zhao Y, Xu H, Zheng Y, Yu Y, Liu S and Cao X. Phosphatase SHP-1 promotes TLR- and RIG-I-activated production of type I interferon by inhibiting kinase IRAK-1. Nat Immunol. 2008; 9(5):542-550.

25.  An H, Zhao W, Hou J, Zhang Y, Xie Y, Zheng Y, Xu H, Qian C, Zhou J, Yu Y, Liu S, Feng G, Cao X. SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type I interferon and proinflammatory cytokine production. Immunity. 2006; 25:919-928.

26.  Zhang M, Tang H, Guo Z, An H, Zhu X, Song W, Guo J, Huang X, Chen T, Wang J, Cao X. Splenic stroma drives mature dendritic cells to differentiate into regulatory dendritic cells. Nat Immunol. 2004; 5(11):1124-1133. (cover story)

Reviews and Comments

1.   Cao X. Intestinal inflammation induced by oral bacteria. Science. 2017; 358(6361):308-309.

2.   Qian C, Cao X. Dendritic cells in the regulation of immunity and inflammation. Semin Immunol. 2017 Dec 11. pii: S1044-5323(17)30043-X. doi:10.1016/j.smim.2017.12.002. [Epub ahead of print]

3.   Zhang X, Liu J, Cao X. Metabolic control of T-cell immunity via epigenetic mechanisms. Cell Mol Immunol. 2017 Oct 30. doi: 10.1038/cmi.2017.115. [Epub ahead of print]

4.   Cao X. Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat Rev Immunol. 2016; 16(1):35-50.

5.   Liu J, Qian C, Cao X. Post-translational modification control of innate immunity. Immunity. 2016; 45(1):15-30.

6.   Liu Y, Cao X. Characteristics and significance of the pre-metastatic niche. Cancer Cell. 2016; 30(5):668-681.

7.   Cao X. Integrative strategy for improving cancer immunotherapy. J Mol Med (Berl). 2016; 94(5):485-487.

8.   Cao X. A call for global research on non-communicable diseases. Lancet. 2015; 385(9967):e5-6.

9.    Liu Y, Cao X. Organotropic metastasis: role of tumor exosomes. Cell Res. 2015; 26(2):149-150. 

10.    Liu J, Cao X. Regulatory dendritic cells in autoimmunity: A comprehensive review. J Autoimmun. 2015; 63:1-12.