Cancer Immunology, Inflammation and Tolerance


Kebin Liu


Kebin Liu, PhD

Cancer Immunology, Inflammation and Tolerance Program
Professor of Biochemistry and Molecular Biology
Professor of Graduate Studies



Georgia Cancer Center
1410 Laney Walker Blvd., CN 1173
Office: 706-721-9483
Lab: 706-721-9958
KLIU@augusta.edu

RESEARCH SUMMARY

The research program in my laboratory focuses on the dynamic interactions between tumor cells and immune cells in the microenvironment. We study tumor cell apoptosis resistance in the context of tumor immune evasion, and how myeloid suppressive cells interact with tumor cells and T cells to promote tumor progression. Our objective is to develop molecular mechanism-based therapy to enhance the efficacy of cancer immunotherapy.

RESEARCH INTERESTS

Genetic and epigenetic regulation of PD-1 and PD-L1 in immune and cancer cells  

Pancreatic and colorectal cancers (except for the MSI subtype) are two of the few human cancers where anti-PD-L1/PD-1 immunotherapy has been unsuccessful. What distinguishes pancreatic and colorectal cancers from other human cancers immunologically is currently unknown. Immune checkpoint inhibitor-based cancer immunotherapy acts through reversing immune suppression to activate tumor-reactive cytotoxic T lymphocytes (CTLs) to lyse tumor cells. It is known that apoptosis resistance is a hallmark of human cancer. If the target tumor cells are not sensitive to apoptosis induction, then regardless of how potent the CTLs are, the tumor cells are not going to be killed. Therefore, our central hypothesis is that pancreatic and colorectal cancer cells possess an apoptosis-resistant phenotype to resistant immune checkpoint inhibitor immunotherapy. Our research focus is two-fold: 1) the molecular mechanism underlying PD-L1 expression in tumor cells and PD-1 expression in CTLs in the tumor microenvironment; and 2) the molecular mechanism underlying dysregulation of pancreatic and colorectal cancer cell death pathways, particularly the Fas-mediated cell death pathways. Our objective is to develop molecular target-based therapy to sensitize pancreatic and colorectal cancer to anti-PD-1/PD-L1 immunotherapy.

Expression regulation and function of IRF8 in immune and cancer cells

IRF8 is a transcription factor of the interferon regulatory factor family, which also includes IRF1, IRF2, IRF3, IRF4, IRF5, IRF6, IRF7, and IRF9. Unlike other members of the family, IRF8 has for decades been thought to be restricted to cells of the myeloid and lymphoid lineages (i.e., hematopoietic lineages). We discovered for the first time that IRF8 is constitutively expressed in certain human colon epithelial and cancer cells. Furthermore, IRF8 is also inducible by IFNg in colon cancer and other types of cancer cells. We determined that IRF8 is a key apoptosis regulator. Furthermore, we also determined for the first time that the IRF8 promoter DNA is often hypermethylated in human and mouse colon carcinoma cells. Our findings that IRF8 functions as an apoptosis regulator and IRF8 expression is silenced by DNA methylation in colon carcinoma cells have since been validated and extended to other types of human cancers and normal epithelial cells by other investigators. Our current interests are two-fold: 1) IRF8 expression regulation and function in T cells and myeloid-derived suppressor cells (MDSCs); and 2) IRF8 function in colon epithelial inflammation and suppression of epithelial cell transformation.  

Epigenetic and immune regulation of colon cancer stem cell homeostasis and cancer chemoresistance and immune evasion

Cancer stem cells/initiating cells, including colon cancer stem cells, were initially considered to be a subset of undifferentiated tumor cells with well-defined phenotypic and molecular markers. However, emerging evidence indicates instead that colon cancer stem cells are heterogeneous subsets of tumor cells that are continuously reshaped by the dynamic interactions between genetic, epigenetic, and immune factors in the tumor microenvironment. Thus, the colon cancer stem cell phenotypes and responsiveness to chemotherapy may not only be a tumor cell-intrinsic feature, but also depend on tumor-extrinsic microenvironment factors. Furthermore, emerging evidence also implicates colon cancer stem cells in potential immune evasion. Our objective is to understand how colon cancer stem cell-intrinsic mechanisms cooperate with the extrinsic microenvironment factors to dynamically shape colon cancer stem cell resistance to chemotherapy and immunotherapy. 

Functions of NF-κB as a molecular link between immune cells and cancer cells in the tumor microenvironment

A low level of NF-kB activity is constitutively present in many types of human cancer cells, and NF-kB activation often promotes tumor growth and progression, providing a strong rationale for anticancer strategies that inhibit NF-kB signaling. However, compelling experimental data, including our data, have shown that NF-kB also acts to promote apoptosis in multiple types of cells. The pro-apoptotic function of NF-kB in the death receptor-mediated apoptosis pathway has been well demonstrated in tumor cells. The molecular mechanisms underlying these contrasting functions of NF-kB in cell death and proliferation is currently unknown. Our interest is to test the hypothesis that the subunit composition of NF-kB protein complexes determines NF-kB functions in cancer cell apoptosis and survival, and also in T cell activation and effector function.

Development of ceramide mechanism-based cancer immunotherapy

Compelling experimental data from mouse models and human patients have shown that sphingolipid deregulation, namely the balance between ceramide and S1P, is a key factor in tumor pathogenesis, progression and cancer cell resistance to chemotherapeutic agents and radiation. The crucial roles of ceramide in tumor development and cancer cell responses to therapy have led to extensive efforts to target the ceramide metabolism pathways for anticancer therapy. We have been performing studies to elucidate the molecular mechanism underlying regulation of ceramidase expression in cancer cells. We have also been collaborating with a chemist and a structural biologist to design molecular target-selective ceramide analogs as enhancers of CTL-based cancer immunotherapy. It is well known that ceramide regulates Fas receptor clustering and Fas-mediated apoptosis. Therefore, our objective is to develop ceramidase-specific inhibitors and/or ceramide analogs that specifically regulate Fas function in cancer cells to enhance the efficacy of FasL+ CTL-based cancer immunotherapy.

RECENT PUBLICATIONS

Chunwan Lu and Kebin Liu. 2017. Epigenetic regulation of PD-L1 expression and pancreatic cancer response to checkpoint immunotherapy. Transl Cancer Res. 6(Suppl 3):S652-S654.

Priscilla S. Redd, Mohammed Ibrahim, Sarah K. Sharman, Amy V. Paschall, Dafeng Yang, and Kebin Liu. 2017. Setd1b compensates loss of IRF8 expression to activate iNOS expression in myeloid-derived suppressor cells. Cancer Res. 77:2834-2843.

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.

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 (JNCI). 109:djw283.

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.

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.

Amy V. Paschall, Dafeng Yang, Chunwan Lu, Priscilla S. Redd, Jeong-Hyeon Choi, Christopher M. Heaton, Jeffrey R. Lee, Asha Nayak-Kapoor, Kebin Liu. 2016. CD133+CD24lo defines a 5-Fluorouracil-resistant colon cancer stem cell-like phenotype. Oncotarget. 7:78698-78712.

Amy V. Paschall, Kebin Liu. 2016. An Orthotopic Mouse Model of Spontaneous Breast Cancer Metastasis. J Vis Exp. 114. doi: 10.3791/54040.

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. Rep. 6:30816 doi:10.1038/srep30816.

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. doi: 10.18632/oncotarget.8246.

Priscilla S. Simon, Sarah K. Sharman, Chunwan Lu, Dafeng Yang, Amy V. Paschall, Sidhartha S. Tulachan and Kebin Liu. 2015. The NF-kB p65 and p50 homodimer cooperate with IRF8 to activate iNOS transcription. BMC Cancer. 15:770.

Amy V. Paschall and Kebin Liu, 2015. Epigenetic and Immune Regulation of Colorectal Cancer Stem Cells. Curr Colorectal Cancer Rep. 11:414-421.

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. Immunol. 195:1868-82.

Amy V. Paschall and Kebin Liu. 2015. Epigenetic Regulation of Apoptosis and Cell Cycle Regulatory Genes in Human Colon Carcinoma Cells. Genomics Data. 5:189-191.

Kankana Bardhan, Amy V. Paschall, Dafeng Yang, May R. Chen, Priscilla S. Simon, Yangzom D. Bhutia, Pamela M. Martin, Muthusamy Thangaraju, Darren D. Browning, Vadivel Ganapathy, Christopher M. Heaton, Keni Gu, Jeffrey R. Lee, and Kebin Liu. 2015. IFNγ induces DNA methylation-silenced GPR109A expression via pSTAT1/p300 and H3K18 acetylation in colon cancer. Cancer Immunol. Res. 3:795–805.

Geming Lu, Ruihua Zhang, Shuo Geng, Liang Peng, Padmini Jayaraman, Chun Chen, Jianjun Yang, Qin Li, Hao Zheng, Kimberly Shen, Juan Wang, Xiyu Liu, Weidong Wang, Chen-Feng Qi, Feihong Xu, Kebin Liu, Sergio Lira, John He, Andrew Sikora, Liwu Li, Zihan Zheng, Chuanping Si, and Huabao Xiong. 2015. Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization. Nature Comm. 6:6676.

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. Immunol. 194:2369-79.

Complete List of publications:

FUNDING

VA 1I01BX001962. 2014-2017                                                                           

NCI 1R01CA182518. 2014-2019

NCI 2R01CA133085. 2008-2020

RESEARCH TEAM

photo of Dafeng Yang
Dafeng Yang

Research Manager                
photo of Chunwan Lu 
Chunwan Lu 

Research Assistant Scientist 
photo of Priscilla S. Redd 
Priscilla S. Redd 

Graduate Student