The laboratory has been focused during the last year on immune-mediated tumor cell destruction. Natural killer (NK) cells and cytotoxic T cells (CTL) lyse virally-infected and tumor cells by 2 main mechanisms:(1) the exocytosis of lytic granules and (2) the expression of cytotoxic molecules like tumor necrosis factor (TNF) or related molecules like Fas-ligand. We have investigated the importance of these mechanisms in cytotoxic immune responses to a murine renal cancer Renca. Using activated T cells from mutant or gene-targeted mice as effector cells, we could demonstrate the lysis of various murine cancer cells in long-term cytotoxicity assays. T cells exclusively used Fas ligand or perforin/granzymes to lyse mouse renal cancer cells. Furthermore, the lysis of the Renca tumor by Fas ligand was not blocked effectively by caspase inhibitors. This is unusual, so the molecular mechanism of tumor cell lysis is currently under investigation. Furthermore, we successfully isolated mouse T cells which specifically killed Renca tumor cells. These specific anti-Renca T cells showed some therapeutic efficacy when transfered to tumor bearing mice in vivo. The cytolytic granules of cytotoxic lymphocytes contain a variety of unique proteins, including a pore-forming protein (perforin) and a family of serine protease enzymes called granzymes. We have further studied the expression of granzyme M (met-ase), a novel granzyme that we had previously cloned. Using a monoclonal antibody specific for granzyme M we have detected this granzyme in freshly isolated NK cells, NKT cells and T gamma delta cells by western blotting and immunohistochemistry. T alpha beta cells do not seem to express this granzyme even after activation. The expression pattern of Granzyme M contrasts with that of the other granzymes and perforin, which can be easily detected in activated T alpha beta cells. This suggests that Granzyme M may be involved in innate rather than adaptive immunity. We are trying to define the biological role of this enzyme, and will soon be obtaining mice where granzyme M has been ablated by gene targeting.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010012-05
Application #
6433177
Study Section
(LEI)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2000
Total Cost
Indirect Cost
Name
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
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
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
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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