title: Specific tumor memory induced by polyethylene-glycol-modified interleukin-2 requires both helper and cytotoxic T cells.
abstract: Local polyethylene-glycol (PEG)-modified interleukin-2 (IL-2) immunotherapy of the guinea pig Line 10 (L10) tumor was previously demonstrated to evoke long-lasting systemic immunity after cure of the tumor and metastases. 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 obtained from the primary tumor site, the regional lymph node or the spleen when isolated during (days 21 and 28) intratumoral treatment with 200,000 IU PEG-IL-2. These data confirm our earlier results obtained with 60,000 IU PEG-IL-2. Moreover, no cytolytic activity was observed in the chromium-release assay after in vitro restimulation with irradiated tumor cells. Specific L10 immunity can be transferred using spleen cell suspensions. Depletion of such a suspension of helper T cells resulted in rejection of the primary tumor in two out of four animals, but all the guinea pigs developed lymph node metastases. Removal of the cytotoxic/suppressor phenotype caused rejection of the dermal tumor in four of eight guinea pigs, but the capacity to prevent lymph node metastases was retained in all animals. Thus, depletion of either subtype reduces, but does not abrogate, the capacity to transfer L10 immunity with spleen cells. In conclusion, our data suggest that tumor cell killing through direct T cell cytotoxicity is not the main mode of action in PEG-IL-2-induced L10 tumor regression. PEG-IL-2 therapy induces early systemic immunity, resulting in rejection of a distant tumor, and the transfer of this immunity depends mainly on the presence of helper T cells, although cytotoxic T cells may also play a role.
authors.affiliation: Laboratory for Pathology, National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands.
authors.forename: L T
authors.initials: LT
authors.lastname: Balemans
authors.forename: P A
authors.initials: PA
authors.lastname: Steerenberg
authors.forename: B H
authors.initials: BH
authors.lastname: Kremer
authors.forename: F J
authors.initials: FJ
authors.lastname: Koppenhagen
authors.forename: P H
authors.initials: PH
authors.lastname: De Mulder
authors.forename: W
authors.initials: W
authors.lastname: Den Otter
mesh_terms: D000818:Animals; D003602:Cytotoxicity, Immunologic; D005260:Female; D006084:Graft Rejection; D006168:Guinea Pigs; D007116:Immunization, Passive; D007156:Immunologic Memory; D007167:Immunotherapy; D007376:Interleukin-2 / Q000031:analogs & derivatives*; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D008213:Lymphocyte Activation; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols / Q000737:chemistry*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D013997:Time Factors
chemical_list: D007376:Interleukin-2; D011092:Polyethylene Glycols