SPECIFIC TUMOR MEMORY INDUCED BY POLYETHYLENE-GLYCOL-MODIFIED INTERLEUKIN-2 REQUIRES BOTH HELPER AND CYTOTOXIC T-CELLS

Local polyethylene-glycol (PEG)-modified interleukin-2 (IL-2) immunoth erapy of the guinea pig Line 10 (L10) tumor was previously demonstrate d to evoke long-lasting systemic immunity after cure of the tumor and metastase. T cells, most likely the helper T cell subpopulation, were demonstrated to be crucial to the antitumor effects. Here we show that systemic immunity is induced within 7 days after the start of PEG-IL- 2 therapy, indicating a rapid systemic priming of L10-specific T cells . No in vitro cytotoxic activity was detected in cell suspensions obta ined from the primary tumor site, the regional lymph node or the splee n when isolated during (days 21 and 28) intratumoral treatment with 20 0000 IU PEG-IL-2. These data confirm our earlier results obtained with 60000 IU PEC-IL-2. Moreover, no cytolytic activity was observed in th e chromium-release assay after in vitro restimulation with irradiated tumor cells. Specific L10 immunity can be transferred using spleen cel l suspensions. Depletion of such a suspension of helper T cells result ed in rejection of the primary tumor in two out of four animals, but a ll the guinea pigs developed lymph node metastases. Removal of the cyt otoxic/suppressor phenotype caused rejection of the dermal tumor in fo ur of eight guinea pigs, but the capacity to prevent lymph node metast ases was retained in all animals. Thus, depletion of either subtype re duces, but does not abrogate, the capacity to transfer L10 immunity wi th spleen cells. In conclusion, our data suggest that tumor cell killi ng through direct T cell cytotoxicity is not the main mode of action i n PEG-IL-2-induced L10 tumor regression. PEG-IL-2 therapy induces earl y systemic immunity, resulting in rejection of a distant tumor, and th e transfer of this immunity depends mainly on the presence of helper T cells, although cytotoxic T cells may also play a role.