Research interests: Cytotoxic T lymphocytes and cancer immunosurveillance; apoptosis resistance, immune evasion and tumor escape/progression; epigenetic regulation of tumor suppressor gene

The Liu Laboratory                                                     

                                                                           research opportunities

Education

BS          1983  Central China Agricultural University, P.R. China

MS          1986  Zhejiang University, Hangzhou, P.R. China

PhD         1988  Zhejiang University, Hangzhou, P.R. China

PhD         1997  University of Oklahoma, Norman, Okla.

Current Research

The immune system constantly detects and eliminates proneoplastic cells long before the development of clinical cancer. Tumor-specific immune responses can also be induced in cancer-bearing hosts via active or adaptive immunotherapy, yet tumors still develop in an immune-competent host, and complete tumor eradication occurs infrequently in vivo. The biologic failure of the immune system to effectively suppress neoplastic disease in immune-competent hosts is not fully understood and has remained a fundamental paradox of tumor immunobiology. Cytotoxic T lymphocytes (CTLs) are the primary effector cells against tumor cells and function primarily through two effector mechanisms. The first cytolytic pathway depends on the polarized secretion of perforin and granzymes. The second effector mechanism involves the interaction of FasL on activated CTLs with its receptor Fas on the target tumor cells. Recent studies have demonstrated that the perforin effector mechanism of tumor-specific CTLs can be selectively suppressed by immune suppressive Treg cells in vivo, whereas acquisition of resistance to Fas-mediated apoptosis is a hallmark of metastatic tumors. Therefore, both the perforin and Fas pathways can be impaired in the tumor microenvironment. Accordingly, suppression of immunosuppression, sensitization of tumor cells to Fas-mediated apoptosis or targeting additional anti-tumor cytotoxic pathways is essential for CTL-based immunotherapy against cancer.

IRF8 function in apoptosis and metastasis.

We have recently identified Interferon Regulatory Factor 8 (IRF8, also known as Interferon Consensus Sequence-Binding Protein or ICSBP) as an essential regulator of the Fas-mediated apoptosis in multiple carcinomas. IRF8 regulates apoptosis by directly regulating Fas and FLIP expression. We have further determined that IRF8 is frequently silenced through its promoter DNA methylation in human colorectal carcinoma, especially in metastatic colorectal carcinoma. Therefore, tumor cells, particularly metastatic cells, use epigenetic mechanisms to silence IRF8 expression to acquire an apoptosis-resistant phenotype to escape from the immune system, resulting in enhanced metastatic capability. Thus our current efforts are put on elucidating the molecular mechanisms underlying epigenetic regulation of IRF8 expression in metastatic colorectal carcinoma cells for the pursuit of combinational therapy involving IRF8 mechanism-based sensitization of metastatic tumor cells to apoptosis and CTL-based immunotherapy for the intervention of colon cancer metastasis.

LTβR-mediated signaling pathways in inflammation and tumor rejection.

Another area of our research program is to study the function of LTβR-mediated signaling pathways in inflammation and apoptosis. The LTβR was initially identified to be critical for the organization of lymphoid tissues, lymph nodes and Peyer’s patches during embryogenesis and development and maintenance of secondary lymphoid architecture in adults. However, it is increasingly appreciated that the LTβR is a two-edged sword that initiates signals leading to both inflammation-mediated survival and apoptosis in tumor cells. There are two known ligands that engage the LTβR under physiological conditions to initiate signaling transduction. The first one is LTα1LTβ2, a cell membrane-anchored heterotrimeric complex of one LTα and two LTβ proteins. The second ligand, LIGHT (LT-related-Inducible ligand that competes for Glycoprotein D binding to Herpesvirus entry mediator on T cells) is a cell-bound homotrimeric protein complex that is also capable of binding to herpes simplex virus entry mediator (HVEM). LTα1LTβ2 is expressed in activated T cells, NK cells and monocytes, whereas LIGHT is only expressed in activated T cells. We have shown that tumor-specific CTLs can destroy target tumor cells through the LTβR-mediated apoptosis in a perforin- and Fas-independent manner. Because the perforin and Fas pathways are frequently impaired in the tumor microenvironment, utilization of LTβR-mediated cytotoxicity may have great potential toward developing an effective approach to bypass immunosuppression of the immune cells and overcome apoptosis resistance of the tumor cells in cancer immunotherapy. Our current study focus is the molecular mechanisms underlying activation of the LTβR-mediated signaling pathways during immune cell-tumor cell interaction in the tumor microenvironment. The long-term objective is to develop a therapeutic strategy to inhibit the LTβR-mediated inflammation to enhance the LTβR-mediated apoptosis and thereby increasing the efficacy of CTL-based cancer immunotherapy.

Model of immune cell-tumor cell interaction.

When tumor cells (orange) arise in normal tissue, an inflammatory response is induced which attracts immune cells (green) migrating to the tumor site. Interactions between immune cells and tumor cells involve direct cell-cell physical contact and release of modulator molecules, primarily cytokines and chemokines. In this life and death battle, on the one hand, the immune cells may prevail and eradicate the tumor cells. On the other hand, tumor cells can counterattack the immune cells by producing inhibitory molecules, activating the immune suppressive cells or acquiring apoptosis-resistant mechanisms to avoid destruction by the immune system. Thus, the anti-tumor immune response can be a two-edged sword and can result in both positive and negative consequences.

Key References:

Yang D, Wang S, Brooks C, Dong Z, Schoenlein P, Kumar V, Ouyang X, Xiong H, Lahat G, Hayes-Jordan A, Lazar A, Pollock R, Lev D, Liu K. IFN Regulatory Factor 8 Sensitizes Soft Tissue Sarcoma Cells to Death Receptor–Initiated Apoptosis via Repression of FLICE-like Protein Expression. Cancer Res. 2009 Feb 1;69(3):1080-8.

McGough JM, Yang D, Huang S, Georgi D, Hewitt SM, Röcken C, Tänzer M, Ebert Matthias PA, Liu K. DNA Methylation Represses IFN-g-induced and STAT1-mediated IRF8 Activation in Colon Carcinoma Cells. Mol Cancer Res. 2008;6:1841-51.
   

Yang D, Stewart TI, Smith KK, Georgi  D, Abrams SI, Liu K. Downregulation of IFN-gR in Association with Loss of Fas Function is Linked to Tumor Progression. Int. J. Cancer. 2008;122:350-62.

Bhatt K, Feng L, Pabla N, Liu K, Smith S, Dong Z. Effects of targeted Bcl-2 expression in mitochondria or endoplasmic reticulum on renal tubular cell apoptosis. Am J. Physiol. Renal Physiol. 2008;294:F499-F507.

Kwon I-K, Schoenlein PV, Delk J, Liu K, Thangaraju M, Dulin N, Ganapathy V, Berger F, Browning DD. Expression of PKG in Metastatic Colon Carcinoma Cells Blocks Tumor Angiogenesis. Cancer. 2008;112:1462-70.

Greeneltch KM, Schneider M, Steinberg SM, Liewehr DJ, Stewart TJ, Liu K, Abrams S. Host Immunosurveillance Controls Tumor Growth via IRF-8-Dependent Mechanisms. Cancer Res. 2007;67:10406-16.

Yang D, Thangaraju M, Browning DD, Dong Z, Korchin B, Lev DC, Ganapathy V, Liu K. Interferon Regulatory Factor 8 Mediates Apoptosis in Non-hemopoietic Tumor Cells via Regulation of Fas Expression. J. Immunol. 2007;179:4775-82.

Yang D, ud Din N, Browning DD, Abrams SI, Liu K. Targeting Lymphotoxin b Receptor with Tumor-SpecificT Lymphocytes for Tumor Regression. Clin Cancer Res. 2007;13:5202-10.

Yang D, Thangaraju M, Greeneltch K, Browning DD, Schoenlein PV, Tamura T, Ozato K, Ganapathy V, Abrams SI, Liu K. Repression of IRF8 by DNA Methylation is a Molecular Determinant of Apoptotic Resistant and Metastatic Phenotype in Metastatic Tumor Cells. Cancer Res. 2007;67:3301-9.

Ohta A, Gorelik E, Prasad S, Ronchese F, Lukashev D, Wong M, Huang X, Caldwel S, Liu K, Smith P, Chen J-F, Jackson E, Apasov S, Abrams S, Sitkovsky M. A2A Adenosine Receptor Protects Tumors From Anti-tumor T cells. Proc. Natl. Acad. Sci. USA. 2006;103:13132-7.

Liu K*, Caldwell* SA, Greeneltch K, Yang D, Abrams S. CTL Adoptive Immunotherapy Concurrently Mediates Tumor Regression and Tumor Escape. J. Immunol. 2006;176:3374-82. (* equal contribution).

Liu K, Caldwell SA , Abrams SI. Immune selection and emergence of aggressive tumor variants as negative consequence of Fas-mediated cytotoxicity and altered IFNg-regulated gene expression. Cancer Res. 200565:4376-88.

Liu K, Caldwell S, Abrams S. Cooperative disengagement of Fas and ICAM-1 in neoplastic cells confers enhanced colonization efficiency. Cancer Res.2005; 65:1045-54.

Liu K, McDuffie E, Abrams SI. Exposure of human Primary Colon Carcinoma Cells to Anti-Fas Interactions Influences the Emergence of Pre-existing Fas-Resistant Metastatic Subpopulations. J. Immunol. 2003;171:4164-74.

Liu K, Abrams SI. Coordinate Regulation of ICSBP and Caspase-1 in the Sensitization of Human Colon Carcinoma Cells to Fas-Mediated Apoptosis by IFN-g. J. Immunol 2003;170:6329-37.

Liu K, Abrams SI. Alterations in Fas Expression are Characteristic of, but not Solely Responsible for, Enhanced Metastatic Competence. J. Immunol. 2003;170:5973-80.

Chakraborty M, Abrams SI, Camphausen K, Liu K, Scott T, Coleman CN, Hodge JW. Irradiation of Tumor Cells Upregulates Fas, Enhances CTL Lytic Activity and CTL Adoptive Immunotherapy. J. Immunol. 2003;170:6338-47.

Liu K, Catalfamo M, Li Y, Henkart PA, Weng N. IL15 mimics T cell receptor crosslinking in the induction of cellular proliferation, gene expression, and cytotoxicity in CD8+ memory T cells. Proc. Natl. Acad. Sci. USA. 2002;99:6192-7.

Liu K, Li Y, Prabhu V, Young L, Becker K, Munson P, Weng N-P. Augmentation in Expression of Activation-induced Genes Differentiates Memory from Naïve CD4+ T Cells and Is a Molecular Mechanism of Enhanced Cellular Response of Memory CD4+ T Cells. J. Immunol. 2001;166:7335-44.

Liu K, Hodes RJ, Weng N-P. Cutting Edge:Telomerase activation in human T lymphocytes does not require increase in telomerase reverse transcriptase (hTERT) protein but is associated with hTERT phosphorylation and nuclear Translocation. J. Immunol. 2001;166:4826-30.

Liu K, Schoonmaker MM, Levine BL, June CH, Hodes RJ, Weng N-P. Constitutive and regulated expression of telomerase reverse transcriptase (hTERT) in human lymphocytes. Proc. Natl. Acad. Sci. USA. 1999;96:5147-52.

Liu K, Li G. Catalytic domain of the p120 Ras GAP binds to Rab5 and stimulates its GTPase activity. J. Biol. Chem. 1998;273:10087-90.

Hanna MM, Liu K. Nascent RNA in transcription complexes interacts with CspE, a small protein in E. coli implicated in chromatin condensation. J. Mol. Biol. 1998; 282:227-39.

Liu K, Zhang Y, Severinov K, Das A, Hanna MM. Role of Escherichia coli RNA polymerase alpha subunit in mudulation of pausing, termination and anti-termination by transcription elongation factor NusA. 1996;The EMBO J. 15:150-61.

Liu K, Somerville S. Cloning and characterization of a highly repeated DNA sequence in Hordeum vulgare L. Genome. 1996;39:1159-68.

Liu K, Hanna MM. NusA contacts nascent RNA in Escherichia coli transcription complexes. J. Mol. Biol. 1995;247:547-58.

Liu K, Hanna MM. NusA interferes with interactions between the nascent RNA and the C-terminal domain of the alpha subunit of RNA polymerase in Escherichia coli transcription complexes. Proc. Natl. Acad. Sci. USA. 1995;92:5012-16.

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