The laboratory has been focused during the last year on immune-mediated tumor cell destruction. Natural killer (NK) cells and cytotoxic T cells (CTL) have the ability to lyse virally-infected and tumor cells. There are two proposed major mechanisms whereby they accomplish this (1) the exocytosis of lytic granules and (2) the expression of cytotoxic molecules like tumor necrosis factor (TNF) or a related molecule known as Fas-ligand. The cytolytic granules contain a variety of unique proteins, including a pore-forming protein (perforin) and a family of serine protease enzymes (granzymes). We have previously identified, sequenced and cloned 2 novel members of the granzyme family which cleaves synthetic substrates after the amino acids arginine or lysine (tryptase-2) and methionine (met-ase). We have developed specific polyclonal antisera to the met-ase and are currently trying to determine its cellular distribution in a variety of leukocyte subsets. Preliminary evidence suggests that this enzyme may be restricted in its expression to NK cells. We are also trying to define the biological role of these enzymes. In addition, we have investigated immune-mediated destruction of a murine renal cancer Renca. We found that the proinflammatory cytokines interferon gamma and tumor necrosis factor enhance Fas expression on Renca cells. Furthermore, this increased surface expression correlates with a dramatic increase in the sensivity of these cells to Fas ligand mediated apoptosis. There is synergistic interaction between the cytokines for both increases in Fas expression and susceptibility to apoptosis. We are currently investigating whether such effects play an important role in immune-mediated rejection of Renca in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010012-02
Application #
6161104
Study Section
Special Emphasis Panel (LEI)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Sun, Kai; Li, Minghui; Sayers, Thomas J et al. (2008) Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation. Blood 112:1522-9
Cretney, Erika; Shanker, Anil; Yagita, Hideo et al. (2006) TNF-related apoptosis-inducing ligand as a therapeutic agent in autoimmunity and cancer. Immunol Cell Biol 84:87-98
Sayers, Thomas J; Murphy, William J (2006) Combining proteasome inhibition with TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) for cancer therapy. Cancer Immunol Immunother 55:76-84
Khan, Tahira; Stauffer, Jimmy K; Williams, Rebecca et al. (2006) Proteasome inhibition to maximize the apoptotic potential of cytokine therapy for murine neuroblastoma tumors. J Immunol 176:6302-12
Sun, Kai; Wilkins, Danice E C; Anver, Miriam R et al. (2005) Differential effects of proteasome inhibition by bortezomib on murine acute graft-versus-host disease (GVHD): delayed administration of bortezomib results in increased GVHD-dependent gastrointestinal toxicity. Blood 106:3293-9
Brooks, Alan D; Sayers, Thomas J (2005) Reduction of the antiapoptotic protein cFLIP enhances the susceptibility of human renal cancer cells to TRAIL apoptosis. Cancer Immunol Immunother 54:499-505
Sedelies, Karin A; Sayers, Thomas J; Edwards, Kirsten M et al. (2004) Discordant regulation of granzyme H and granzyme B expression in human lymphocytes. J Biol Chem 279:26581-7
Sun, Kai; Welniak, Lisbeth A; Panoskaltsis-Mortari, Angela et al. (2004) Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib. Proc Natl Acad Sci U S A 101:8120-5
Takeda, Kazuyoshi; Yamaguchi, Noriko; Akiba, Hisaya et al. (2004) Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy. J Exp Med 199:437-48
Smyth, Mark J; Swann, Jeremy; Kelly, Janice M et al. (2004) NKG2D recognition and perforin effector function mediate effective cytokine immunotherapy of cancer. J Exp Med 200:1325-35

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