In vivo characterization of immunogenicity of a mitoxantrone-resistant murine P388 leukemia
Fichtner, I.; Reipert, B.; Becker, M.; Lemm, M.
In Vivo 7(1): 73-79
1993
ISSN/ISBN: 0258-851X PMID: 8504210 Document Number: 409647
The Mitoxantrone-resistant murine leukemia P388/Mitox, expressing the multidrug-resistant phenotype, has a higher immunogenicity than the parent sensitive P388. This could be shown in vivo by immunization with lethally-irradiated tumor cells. If the P388/Mitox was used for immunization before subsequent challenge with viable tumor cells of the same line, this resulted in a partial rejection of tumors and production of a substantial number of tumor-free survivors. For an effective immunization at least two primings s.c., i.v. or i.p with at least 10-6 irradiated cells were necessary. This protected the recipient mice from a challenge of up to 10-8 viable cells over a period of at least 75 days. Treatment of BDF-1 mice with The T-cell suppressor Cyclosporin A prevents immunization. In nude mice no immunization effect could be obtained. It was possible to transfer immunity adoptively with spleen cells from mice, which were treated with irradiated tumor cells of the P388/Mitox line. Treatment of tumor-bearing mice with IL-2 resulted in a prolongation of survival both when it was administered prophylactically before transplantation of P388/Mitox and at an advanced stage (day 7-11). Also the alkylphosphocholine hexadecylphosphocholine was significantly effective in the resistant but not in the parent P388 leukemia. The data presented demonstrate that by development of a multidrug-resistance, concomitantly a xenogenization must have taken place which leads to a recognition of cells by immune mechanisms. In our model, T-lymphocytes and NK-/LAK-cells probably play a role in the immunologically conditioned rejection of tumor cells of the P388/Mitox leukemia. Two main conclusions can be drawn on the basis of our results. Firstly, the apparent connection between development of resistance and higher immunogenicity should be taken into consideration in clinical cancers and could be the focus for the creation of more efficient immunotherapeutic protocols. Secondly, with the availability of standardized couples of immunogenic and non-immunogenic tumor models, possibilities exist for in vivo screening of both immunosuppressive and immunostimulating strategies.