MECHANISM OF MELPHALAN-MEDIATED TUMOR ERADICATION

本提案的主要目的是了解

The main objective of this proposal is to understand the mechanism by which a widely used anticancer drug, melphalan (L- PAM); shifts the balance from immunosuppression to potent antitumor immunity when administered to mice at an advanced stage of tumor growth. We know already that the immunomodulatory activity of a low dose of this alkylating agent consists, in some plasmacytoma tumor models, not only of elimination of suppressor cell activity, but also of induction of appearance of immunopotentiating activity in T-cells that coexpress the Lyt 2 and the L3T4 antigens even when these cells reside in secondary lymphoid organs. Experiments will be performed to determine the role of the thymus in the appearance of T cells with such an unusual phenotype (i.e., expressing simultaneously the Lyt 2 and L3T4 antigens) in the spleens of adult tumor-bearing mice shortly after the low dose chemotherapy since (a) greater than or equal to 80% of the lymphocytes within the thymus coexpress both markers, and (b) the low dose L-PAM therapy renders thymocytes from MOPC-315 tumor-bearing mice (but not from normal mice) capable of bringing about the generation of enhanced antitumor cytotoxicity when added to the immunization culture of normal spleen cells and the "autochthonous" tumor. In addition, we will elucidate the effect of the low dose chemotherapy on the cellular composition of the tumor bearer thymus. As part of this study, we will determine the Lyt2 and L3T4 phenotype of the immunologically "active" cells in the thymus of L-PAM treated MOPC-315 tumor bearers as well as elucidate the mechanism by which the low dose L-PAM renders thymocytes from MOPC-315 tumor bearers immunologically "active". In addition, we will determine the mechanism by which these"active" thymocytes bring about the generation of enhanced lytic activity. Emphasis will be placed on extending our observations to other tumor models. For this purpose, we will employ selected plasmacytomas that differ in their immunogenicity. Thus, the results obtained from these experiments will also provide information as to the correlation between tumor cell immunogenicity and the subsequent ability of low dose L-PAM therapy to induce the appearance of "active" cells in the thymus of tumor-bearing mice. Finally, we will determine the importance of the thymus to the curative effectiveness of low dose L-PAM therapy of MOPC-315 or MOPC- 104E tumor bearers since the therapeutic effectiveness of this therapeutic protocol depends on the ability of T-cell-dependent antitumor immunity to eradicate a large tumorigenic load remaining after clearance of the drug from the circulation.