DF/HCC Program Affiliation

Cancer Immunology

Research Abstract

The Lieberman laboratory studies cytotoxic T lymphocytes, key cells in the immune defense against viral infection and cancer, and their role in antiviral immunity.
A major focus of the Lieberman laboratory is studying the molecular pathways used by CTLs to induce cell death. Granzyme A, the most abundant CTL death-inducing protease, induces a novel form of programmed cell death. Many tumors and viruses resistant to the classical pathway of cell death are sensitive to this pathway. The Lieberman laboratory has identified several novel protein substrates of granzyme A and has recently worked out the molecular basis for DNA destruction in this pathway.
Other work centers on understanding how the function of cytotoxic T lymphocytes is regulated. Her laboratory is particularly interested in characterizing the cytotoxic T lymphocyte response to HIV-1, the virus that causes AIDS, and why it does not ultimately control the virus. They have found that although there are a large number of HIV-specific T cells in HIV-infected individuals, their function is significantly compromised in vivo. Knowledge gained from laboratory studies is used to develop and test in small clinical studies immune-based therapeutic and preventive strategies to treat HIV-infection. Currently her laboratory is working to develop an oral HIV vaccine using a Listeria monocytogenes vector.

Her interest in HIV led to recent work to harness RNA interference (RNAi) as a therapeutic tool. Her laboratory was able to harness this ancient antiviral defense mechanism, originally described in plants and worms, but more recently in mammalian cells, to suppress HIV infection. She was the first to demonstrate in an animal model that RNAi could be used to protect animals from disease. Her laboratory is currently actively working on translating RNAi for therapeutic use for HIV and cancer.

More recently they have been studying how miRNAs regulate cell differentiation and cancer. A recent paper from the Lieberman laboratory identified the miRNA let-7 as a master regulator of stemness of breast cancer stem cells. They are currently working to define the pathways by which let-7 and other miRNAs regulate self-renewal, differentiation, cell division, metastasis and chemosensitivity. They are also working to translate these findings into approaches for cancer therapy.

Publications

• Chowdhury D, Beresford PJ, Zhu P, Zhang D, Sung JS, Demple B, Perrino FW, Lieberman J.The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death.Mol Cell 2006 Jul 7;23(1):133-42.
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• Palliser D, Chowdhury D, Wang QY, Lee SJ, Bronson RT, Knipe DM, Lieberman J.An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection.Nature 2006 Jan 5;439(7072):89-94.
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• Keefe D, Shi L, Feske S, Massol R, Navarro F, Kirchhausen T, Lieberman J.Perforin triggers a plasma membrane-repair response that facilitates CTL induction of apoptosis.Immunity 2005 Sep;23(3):249-62.
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• Song E, Zhu P, Lee SK, Chowdhury D, Kussman S, Dykxhoorn DM, Feng Y, Palliser D, Weiner DB, Shankar P, Marasco WA, Lieberman J.Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors.Nat Biotechnol 2005 Jun;23(6):709-17.
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• Martinvalet D, Zhu P, Lieberman J.Granzyme A induces caspase-independent mitochondrial damage, a required first step for apoptosis.Immunity 2005 Mar;22(3):355-70.
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• Song E, Lee SK, Wang J, Ince N, Ouyang N, Min J, Chen J, Shankar P, Lieberman J.RNA interference targeting Fas protects mice from fulminant hepatitis.Nat Med 2003 Mar;9(3):347-51.
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