Studies are proposed to elucidate the physiological function of the B7/CD28 costimulatory pathway in the acquisition of T-cell-dependent tumor-eradicating immunity by hitherto immunosuppressed mice bearing large tumors and extensive metastases. Particular emphasis will be placed on determining if B7-1 and/or B7-2 up-regulation on host cells or on tumor cells is important for the low-dose melphalan-induced acquisition of tumor eradicating immunity by MOPC-315 tumor bearers. In addition, this study will elucidate the mechanisms through which the low-dose chemotherapy leads to up-regulation of B7-1 and/or B7-2 expression by cells identified as important for the low-dose L-PAM-induced acquisition of tumor-eradicating immunity by the hitherto immunosuppressed MOPC-315 tumor bearers. Studies are also proposed to determine why blockade of the B7/CTLA-4 interaction does not offer any therapeutic benefits to MOPC-315 tumor bearers. Specifically, it will test the hypothesis that the failure of anti-CTLA-4 treatment to offer any therapeutic benefits in the MOPC-315 tumor system, is due to the fact that at the time of anti-CTLA-4 administration, the activated T-cells are not predominantly of the type that is involved in the generation/exertion (rather than inhibition) of tumor-eradicating immunity, and the anti-CTLA-4 treatment prevents the shut-off of the activity of both kinds of activated T-cells. In addition, it will be determined if the beneficial effects of anti-CTLA-4 treatment can be realized in the MOPC-315 tumor system when the balance is shifted through external manipulations, towards activated T-cells that are involved in the generation/exertion of tumor-eradicating immunity. Finally, it will be determined if the principles learned from the MOPC-315 tumor model can be extended to a different tumor model. In summary, the studies proposed will provide valuable information regarding the physiological functions of the B7-Cd28/CTLA-4 costimulatory pathway in vivo in mice bearing a large tumor, both before and after the mice are subjected to therapeutic modalities known to lead to the acquisition of tumor-eradicating immunity by the hitherto immunosuppressed tumor bearers. This information will in turn facilitate the design of rational approaches to manipulate this key immunoregulatory pathway to the benefit of the tumor bearers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076532-02
Application #
2896285
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Finerty, John F
Project Start
1998-07-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Donepudi, Manjula; Jovasevic, Vladimir M; Raychaudhuri, Pradip et al. (2003) Melphalan-induced up-regulation of B7-1 surface expression on normal splenic B cells. Cancer Immunol Immunother 52:162-70
Donepudi, M; Raychaudhuri, P; Bluestone, J A et al. (2001) Mechanism of melphalan-induced B7-1 gene expression in P815 tumor cells. J Immunol 166:6491-9
Jovasevic, V M; Mokyr, M B (2001) Melphalan-induced expression of IFN-beta in MOPC-315 tumor-bearing mice and its importance for the up-regulation of TNF-alpha expression. J Immunol 167:4895-901
Sojka, D K; La Motte, R N; Mokyr, M B (2000) B7-2 expression on tumor cells is important for the acquisition of cytotoxic T lymphocyte activity by spleen cells from low-dose-melphalan-treated MOPC-315 tumor bearers via a mechanism that requires either B7-1 or B7-2 expression on host antigen-presenti Cancer Immunol Immunother 49:22-Oct
Sojka, D K; Donepudi, M; Bluestone, J A et al. (2000) Melphalan and other anticancer modalities up-regulate B7-1 gene expression in tumor cells. J Immunol 164:6230-6
Donepudi, M; Quach, D D; Mokyr, M B (1999) Signaling through CD40 enhances cytotoxic T lymphocyte generation by CD8+ T cells from mice bearing large tumors. Cancer Immunol Immunother 48:153-64
Kalinichenko, V V; Mokyr, M B; Graf Jr, L H et al. (1999) Norepinephrine-mediated inhibition of antitumor cytotoxic T lymphocyte generation involves a beta-adrenergic receptor mechanism and decreased TNF-alpha gene expression. J Immunol 163:2492-9
La Motte, R N; Sharpe, A H; Bluestone, J A et al. (1999) Host B7-1 and B7-2 costimulatory molecules contribute to the eradication of B7-1-transfected P815 tumor cells via a CD8+ T cell-dependent mechanism. J Immunol 162:4817-23
Kalinichenko, T V; Mokyr, M B (1998) Limited importance of CD40/CD40L interaction in the B7-dependent generation of anti-MOPC-315 cytotoxic T lymphocyte activity by tumor bearer splenic cells stimulated in vitro in the presence of tumor necrosis factor. Cancer Immunol Immunother 46:293-303

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