The objective of this competitive renewal is to define the role of TNF in murine anti-tumor responses. We will also define the cellular basis of actual and potential TNF-producers at the population and organ level under basal conditions or after stimulation in vivo and in vitro. The in vitro tumor lysis and in vivo-induced local tumor necrosis are two related and well defined activities of TNF. However, most of the animal and human studies showed that administration of recombinant TNF to tumor-bearing hosts had very limited therapeutic effects. In this grant we plan to use three new approaches to define the role of TNF in anti-tumor responses. 1) We will determine if treatment with antibodies that neutralize TNF lytic functions will affect tumor development and behavior. Thus, answering the question on whether TNF has anything to do with anti-tumor responses in vivo. 2) We developed models in which TNF production is selectively induced in vivo. We will determine if these increased levels of soluble TNF and of TNF-producing cells will affect tumor development and behavior. This approach may answer the question on whether endogenous production of TNF rather than exogenous administration offers a therapeutic advantage in anti-tumor responses. And 3) We will determine if membrane-associated TNF (Ma-TNF) rather than soluble TNF (So-TNF) may have a preferential role in the anti-tumor effects. A preferential role of Ma-TNF rather than So-TNF, may also explain the therapeutic failures with exogenous So-TNF. The main in vivo models to be tested are tumor development after chemical carcinogens and behavior of transplanted tumors in syngeneic mice. Mice in both types of models will be treated using protocols that inhibit TNF activity or that induce TNF production in vivo. These in vivo models will be further developed and refined using in vitro triggering of TNF production by T and non-T lymphoid cells by various agents. Our studies will also include the analysis of the in vivo and in vitro behavior of tumor variants selected for high sensitivity or for resistance to TNF in vitro killing. It is felt that the proposed approaches will clarify our understanding of the biology of TNF and its possible use in anti-tumor therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Experimental Immunology Study Section (EI)
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Glickstein, L; Macphail, S; Stutman, O (1996) Uncoupling IL-2 production from apoptosis and TNF production by changing the signal through the TCR. J Immunol 156:2062-7
Shih, S C; Stutman, O (1996) Cell cycle-dependent tumor necrosis factor apoptosis. Cancer Res 56:1591-8
Macphail, S; Stutman, O (1993) H-2 I-E molecules isolated from Mls1a stimulatory cells do not activate Mls1a-responsive T cells but do present exogenous staphylococcal enterotoxins. Eur J Immunol 23:90-5
Hernandez-Caselles, T; Stutman, O (1993) Immune functions of tumor necrosis factor. I. Tumor necrosis factor induces apoptosis of mouse thymocytes and can also stimulate or inhibit IL-6-induced proliferation depending on the concentration of mitogenic costimulation. J Immunol 151:3999-4012
Lattime, E C; Stutman, O (1992) WEHI-164 clone 2F: in vitro antitumor effects of tumor necrosis factor and gamma-interferon. Nat Immun 11:34-45
Lattime, E C; Stutman, O (1991) Antitumor immune surveillance by tumor necrosis factor producing cells. Immunol Res 10:104-13
Lattime, E C; Stutman, O (1989) Tumor growth in vivo selects for resistance to tumor necrosis factor. J Immunol 143:4317-23
Macphail, S; Stutman, O (1988) Anti-L3T4 antibody inhibits the lysis of H-2 class II antigen-negative target cells by L3T4+ cytotoxic T lymphocytes. Proc Natl Acad Sci U S A 85:5205-9
Lattime, E C; Stoppacciaro, A; Khan, A et al. (1988) Human natural cytotoxic activity mediated by tumor necrosis factor: regulation by interleukin-2. J Natl Cancer Inst 80:1035-8
Lattime, E C; Stoppacciaro, A; Stutman, O (1988) Limiting dilution analysis of TNF producing cells in C3H/HeJ mice. J Immunol 141:3422-8

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