Source: https://www.augusta.edu/mcg/bmb/liulabpage.php
Timestamp: 2019-04-23 16:55:49+00:00

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The research program in the Liu Laboratory focuses on the dynamic interactions between tumor cells and immune cells in the tumor microenvironment. At the molecular level, we are interested in elucidating the molecular mechanisms underlying genetic and epigenetic regulation of the expression of Fas, IRF8, PD-L1 and PD-1 in tumor cells and immune cells [e.g., T cells and myeloid-derived suppressor cells (MDSCs)], respectively. At the cellular level, we study the functions of Fas, IRF8, NF-kB p50, PD-L1 and PD-1 in tumor cells and immune cells in the context of T cell activation, immune suppression and tumor immune escape. Various genetically modified mouse models, including mice with global or tissue-specific deficiency/knock out of Fas, Irf8, nfkb1, cd274, pdcd1, Ifnar1 have been used to study tumor cell apoptosis resistance, tumor cell response to targeted therapy and immunotherapy, T cell effector function, and immune suppression. At the translational level, we have been studying T cell activation, MDSC differentiation, and PD-L1 and PD-1 expression and function in human colorectal and pancreatic cancer patients. The long-term objective of our research program is to develop molecular mechanism-based therapies to overcome colorectal and pancreatic cancer non-response to immune checkpoint inhibitor immunotherapy, which is currently the most significant challenge in human colorectal and pancreatic cancer immunotherapy. Specifically, the following research projects are carried out in our laboratory.
MDSCs are a heterogeneous population of myeloid cells of various differentiation stages that are induced under various pathological conditions, including cancer. Massive accumulation of MDSCs is a hallmark of human cancer. One key function of MDSCs is to inhibit effector functions of cytotoxic T lymphocytes (CTLs). Our research project aims at: 1) the molecular mechanism underlying regulation of MDSC differentiation by chronic inflammation and tumor; 2) PD-L1 expression regulation and function in subsets of MDSCs; and 3) development of molecular target-based therapies to suppress MDSC differentiation and/or function in the tumor microenvironment.
1. Mohammed L. Ibrahim, John D. Klement, Chunwan Lu, Priscilla S. Redd, Wei Xiao, Dafeng Yang, Darren D. Browning, Natasha M. Savage, Phillip J. Buckhaults, Herbert C. Morse III, and Kebin Liu. 2018. Myeloid-Derived Suppressor Cells Produce IL-10 to Elicit DNMT3b-Dependent IRF8 Silencing to Promote Colitis-Associated Colon Tumorigenesis. Cell Rep. 2018, 25:3036-3046. PMCID: PMC6319669.
3. Chunwan Lu, Priscilla S Redd, Jeffrey R Lee, Natasha Savage, and Kebin Liu. 2016. The expression profiles and regulation of PD-L1 in tumor-induced myeloid-derived suppressor cells. OncoImmunology. 5:e1247135. PMCID: PMC5214087.
4. Feiyan Liu, Xia Li, Chunwan Lu, Aiping Bai, Jacek Bielawski, Alicja Bielawska, Brendan Marshall, Patricia V Schoenlein, Iryna O. Lebedyeva, and Kebin Liu. 2016. Ceramide activates lysosomal cathepsin B and cathepsin D to attenuate autophagy and induces ER stress to induce myeloid-derived suppressor cell death. Oncotarget. 7:83907-83925. PMCID: PMC5356634.
5. Xiaolin Hu, Kankana Bardhan, Amy V. Paschall, Dafeng Yang, Jennifer L. Waller, Mary Anne Park. Asha Nayak-Kapoor, Thomas A. Samuel, Scott I. Abrams, and Kebin Liu. 2013. Deregulation of Apoptotic Factors Bcl-xL and Bax Confers Apoptotic Resistance to Myeloid-derived Suppressor Cells and Contributes to Their Persistence in Tumors. J. Bio. Chem. 288:19103-19115. PMCID: PMC3696683.
IRF8 expression and function have for decades been thought to be restricted to cells of the myeloid and lymphoid lineages. We discovered that IRF8 is constitutively expressed in human colon epithelial and tumor cells. We determined that IRF8 is a key apoptosis regulator in solid tumor cells. Furthermore, we determined that the IRF8 promoter is often hypermethylated in colon tumor cells. We have recently made a surprising finding that IRF8 expressed in T cells represses GM-CSF expression to suppress CD11b+Gr1+ immature myeloid cell accumulation. We further determined that IRF8 functions as a repressor of osteopontin that acts as a novel immune checkpoint in CTLs. Current effort of this project focuses on: 1) the IRF8-regulated transcriptome in colon epithelial cells and tumor cells in the context of colon tumorigenesis and tumor progression; and 2) molecular mechanisms underlying IRF8 expression and function in myeloid cells in the context of immune suppression.
1. John D. Klement, Amy V. Paschall, Priscilla S. Redd, Mohammed L. Ibrahim, Chunwan Lu, Dafeng Yang, Esteban Celis, Scott I. Abrams, Keiko Ozato, and Kebin Liu. 2018. An Osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion. J Clin Invest. 128:5549-5560. PMCID: PMC6264631.
2. Amy V. Paschall, Ruihua Zhang, Chen-Feng Qi, Kankana Bardhan, Liang Peng, Geming Lu, Jianjun Yang, Miriam Merad, Tracy McGaha, Gang Zhou, Andrew Mellor, Scott I. Abrams, Herbert C. Morse III, Keiko Ozato, Huabao Xiong, and Kebin Liu. 2015. IFN Regulatory Factor 8 Represses GM-CSF Expression in T cells to Affect Myeloid Cell Lineage Differentiation. J. Immunol. 194:2369-79. PMCID: PMC4340766.
3. Xiaolin Hu, Dafeng Yang, Mary Zimmerman, Feiyan Liu, Jine Yang, Swati Kannan, Andreas Burchert, Zdzislaw Szulc, Alicja Bielawska, Keiko Ozato, Kapil Bhalla, and Kebin Liu. IRF8 Regulates Acid Ceramidase Expression to Mediate Apoptosis and Suppresses Myelogeneous Leukemia. Cancer Res. 71:2882-91. PMCID: PMC3078194.
4. Jine Yang, Xiaolin Hu, Mary Zimmerman, Christina M. Torres, Dafeng Yang, Sylvia B. Smith, and Kebin Liu. 2011. IRF8 Regulates Bax Transcription in vivo in Primary Myeloid Cells. Immunol. 187:4426-30. PMCID: PMC3197864.
5. Dafeng Yang, Muthusamy Thangaraju, Darren D. Browning, Zheng Dong, Borys Korchin, Dina C. Lev, Vadivel Ganapathy, and Kebin Liu. 2007. Interferon Regulatory Factor 8 Mediates Apoptosis in Non-hemopoietic Tumor Cells via Regulation of Fas Expression. J. Immunol. 179:4775-4782. PMID:17878376.
Compelling experimental data have determined that NF-kB functions to promote tumor growth and progression. However, targeting NF-kB for human cancer therapy has yet to show efficacy. Using multiple molecular approaches, including EMSA, ChIP, CRISPR, and NF-kB subunit KO mice, we have determined that NF-kB acts as a transcriptional activator of Fas in colon tumor cells in vitro and as a colon tumor suppressor in vivo. We further determined that the p50 NF-kB functions as a transcriptional activator of PD-1 and repressor of Gzmb in T cells, respectively. Ongoing research focuses on: 1) elucidating the molecular mechanisms underlying the contrasting roles of NF-kB in tumor promotion and suppression; and 2) the functions of NF-kB p50 complex in T cell activation and effector function in the tumor microenvironment.
1. Priscilla S. Redd, Chunwan Lu, John D. Klement, Mohammed L. Ibrahim, Gang Zhou, Takumi Kumai, Esteban Celis, and Kebin Liu. 2018. H3K4me3 mediates the NF-κB p50 homodimer binding to the pdcd1 promoter to activate PD-1 transcription in T cells. OncoImmunology. 7:e1483302. PMCID: PMC6140591.
3. Priscilla S. Simon, Kankana Bardhan, May R. Chen, Amy V. Paschall, Chunwan Lu, Roni J. Bollag, Feng-Chong Kong, JianYue Jin, Feng-Ming Kong, Jennifer L. Waller, Raphael E. Pollock, and Kebin Liu. 2016. NF-kB Functions as a Molecular Link between Tumor Cells and Th1/Tc1 T Cells in the Tumor Microenvironment to Exert Radiation-mediated Tumor Suppression. Oncotarget. 7:23395-415. PMCID: PMC5029635.
4. Xiaolin Hu, Mary Zimmerman, Kankana Bardhan, Dafeng Yang, Jennifer L. Waller, Georgia B. Liles, Jeffrey R. Lee, Raphael Pollock, Dina Lev, Carl F. Ware, Ellen Garber, Veronique Bailly, Jeffrey L. Browning, and Kebin Liu. 2013. Lymphotoxin β receptor mediates caspase-dependent tumor cell apoptosis in vitro and tumor suppression in vivo despite induction of NF-kB activation. Carcinogenesis. 34:1105-1114. PMCID: PMC3643415.
5. Dafeng Yang, Najam ud Din, Darren D. Browning, Scott I. Abrams, and Kebin Liu. 2007. Targeting Lymphotoxin β Receptor with Tumor-Specific T Lymphocytes for Tumor Regression. Clin Cancer Res. 13:5202-5210. PMID:17785576.
Fas (also termed CD95) is a cell surface death receptor. The expression of its physiological ligand, the membrane-bound FasL, is restricted to activated T cells and NK cells. The Fas-FasL pathway is one of the two effector cytotoxic pathways that CTL use to kill target cells. Although recent reports imply a role of Fas in tumor promotion, the best known function of Fas is transducing cell death signal. We and others have determined that Fas expression is often downregulated in human colon carcinoma cells, especially in the metastatic colon carcinoma cells. Using genomics approaches, we determined that Fas is silenced by its promoter H3K9me3 deposition. We further determined that CD133+CD24loFaslo defines a colon cancer stem cell-like cell phenotype. Our current focus is: 1) molecular mechanism underlying Fas expression silencing in colon cancer stem cell-like cells and colon cancer resistance to immune checkpoint inhibitor (e.g., anti-PD-1) immunotherapy; and 2) Fas expression and function in tumor-specific CTLs in the tumor microenvironment.
1. Wei Xiao, Mohammed L Ibrahim, Priscilla S. Redd, John D. Klement, Chunwan Lu, Dafeng Yang, Natasha M. Savage, and Kebin Liu. 2018. Loss of Fas Expression and Function is Coupled with Colon Cancer Stem Cell-like Cell Phenotype and Resistance to T Cell Immunotherapy. Mol Cancer Res.
2.Amy V. Paschall, Dafeng Yang, Chunwan Lu, Jeong-Hyeon Choi, Xia Li, Feiyan Liu, Mario Figueroa, Nicholas H. Oberlies, Cedric Pearce, Wendy B. Bollag, Asha Nayak-Kapoor, Kebin Liu. 2015. H3K9 Trimethylation Silences Fas Expression to Confer Colon Carcinoma Immune Escape and 5-Fluorouracil Chemoresistance. J. Immunol. 195:1868-82. PMCID:PMC4530033.
3. Feiyan Liu, Kankana Bardhan, Dafeng Yang, Muthusamy Thangaraju, Vadivel Ganapathy, Jennifer L. Waller, Georgia Liles, Jeffrey R. Lee, and Kebin Liu. 2012. NF-қB Directly Regulates Fas Transcription to Modulate Fas-mediated Apoptosis and Tumor Suppression. J. Biol. Chem. 287:25530-40. PMCID: PMC3408167.
4. Dafeng Yang, Trina I. Stewart, Kimberly, K. Smith, David Georgi, Scott I. Abrams, and Kebin Liu. 2008. Downregulation of IFN-yR in Association with Loss of Fas Function is Linked to Tumor Progression. Int. J. Cancer. 122:350-362. PMID: 7918178.
5. Mary A. Zimmerman, Nur-Taz Rahman, Dafeng Yang, Guy Lahat, Alexander J. Lazar, Raphael Pollock, Dina Lev, and Kebin Liu. 2012. Unphosphorylated STAT1 promotes sarcoma development through repressing expression of Fas and Bad and conferring apoptotic resistance. Cancer Res. 72:4724-32. PMCID: PMC3564959.
Despite the breakthroughs in immune checkpoint inhibitor immunotherapy in many types of human cancers, colon (except for the small MSI subset) and pancreatic cancer do not respond to immunotherapy. One of our research objectives is to translate our findings to colon and pancreatic cancer immunotherapy. We are actively involved in the development of molecular mechanism-based therapies to overcome colon and pancreatic cancer resistance to anti-PD-1 immunotherapy. Our primary targets are: 1) Fas expression and function in tumor cells; 2) PD-L1 expression and function in tumor cells and MDSCs; and 3) CTL effector expression regulation. Both syngeneic mouse tumor models and patient-derived xenograft (PDX) mouse models are used in our drug development process.
1. Chunwan Lu, Dafeng Yang, John D. Klement, II Kyu Oh, Natasha M. Savage, Jennifer L. Waller, Aaron H. Colby, Mark W. Grinstaff, Nicholas H. Oberlies, Cedric J. Pearce, Zhiliang Xie, Samuel K. Kulp, Christopher C. Coss, Mitch A. Phelps, Thomas Albers, Iryna O. Lebedyeva, and Kebin Liu. 2019. SUV39H1 represses the expression of cytotoxic T lymphocyte effectors to promote colon tumor immune evasion. Cancer Immunol. Res.7:414-427.
2. Chunwan Lu, Asif Talukder, Natasha Savage, Nagendra Singh and Kebin Liu. 2017. Jak-STAT-mediated chronic inflammation impairs cytotoxic T lymphocyte activation to decrease anti-PD-1 immunotherapy efficacy in pancreatic cancer. OncoImmunology. 6:e1291106. PMCID: PMC5384417.
3. Chunwan Lu, Amy V. Paschall, Huidong Shi, Natasha Savage, Jennifer L. Waller, Maria E. Sabbatini, Nicholas H. Oberlies, Cedric Pearce, Kebin Liu. 2017. The MLL1-H3K4me3 Axis-Mediated Up-Regulation of PD-L1 Contributes to Pancreatic Cancer Immune Evasion. J Natl Cancer Inst. 109:djw283. PMCID: PMC5291187.
4. Genevieve L. Coe, Priscilla S. Redd, Amy V. Paschall, Chunwan Lu, Lilly Gu, Thomas Albers, Iryna O. Lebedyeva, and Kebin Liu. 2016. Ceramide mediates FasL-induced caspase 8 activation in colon carcinoma cells to enhance FasL-induced cytotoxicity by tumor-specific cytotoxic T lymphocytes. Cell Rep. 6:30816 doi:10.1038/srep30816. PMCID: PMC4973238.
5. Feiyan Liu, Qianqian Liu, Dafeng Yang, Wendy B. Bollag, Keith Robertson, Ping Wu, and Kebin Liu. 2011. Verticillin A Overcomes Apoptosis Resistance in Human Colon Carcinoma through DNA methylation‑dependent Upregulation of BNIP3. Cancer Res. 71:6807-16. PMCID: PMC3206150.
1. US non-provisional patent # 15/455,665. Ceramide Analogs. Filed on March 10, 2017.
2. US non-provisional patent # 16/134,306. Small Molecule Histone Methyltransferase SUV39H1 Inhibitor and Uses Thereof. Filed on September 18, 2018.

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