IMMUNOMODULATION BY ADRIAMYCIN - EFFECT ON THE PRODUCTION OF CYTOTOXIC AND INFLAMMATORY ANTITUMOR IMMUNE-RESPONSES

We have recently demonstrated in a mouse renal adenocarcinoma tumor system that the antitumor effect of adriamycin (ADM) in combination with interleukin-2 (IL2) is superior to treatment with either ADM or IL2 alone. Based on this observation we postulated that modulation of host's immune competence by ADM and/or IL2 may be partly responsible for the antitumor effects of the combination treatment. Indeed, pretreatment with ADM was found to potentiate the production of both cytotoxic and non-cytotoxic immune responses. A single dose of ADM significantly increased the number of nucleated cells in the spleen in a time related fashion. A small but selective increase in CD4+ cells without an apparent change in CD8+ subset of T cells was observed following treatment with ADM. ADM potentiated augmentation of NK activity by IL2, but had no effect on the production of lymphokine activated killer (LAK) cells by IL2. In contrast, treatment with a combination of ADM and IL2 resulted in increased LAK activity and the frequency of LAK-precursors in the spleen. ADM also enhanced the development of tumor specific inflammatory delayed hypersensitivity (DH) response. Mice expressing tumor specific DH were resistant to rechallenge with viable tumor cells and their spleen cells inhibited the tumor growth in a local adoptive transfer assay. Thus, antitumor effects of combined ADM/IL2 treatment may in part involve augmented production of cytotoxic and T cell-mediated inflammatory antitumor immune responses.