B7-CD28/CTLA-4 INTERACTIONS IN IMMUNITY TO TUMORS

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DESCRIPTION (Adapted from the Investigator's Abstract): 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.