Locoregional therapy with polyethylene-glycol-modified interleukin-2 of an intradermally growing hepatocellular carcinoma in the guinea pig induces T-cell-mediated antitumor activity.
Therapy with repeated intratumoral and perilymphatic administration of relatively low doses of polyethylene-glycol(PEG)-modified interleukin-2 (IL-2) in the syngeneic guinea pig line 10 (L10) hepatocarcinoma results in significant local tumor growth inhibition and a delay in development of regional lymph node metastases of more than 3 weeks when compared to controls. Occasionally animals are cured of tumor. The mechanism of this antitumor activity was studied. The antitumor activity of locoregionally administered PEG-IL-2 was abrogated by pretreatment with polyclonal anti-thymocyte serum, indicating that the observed tumor growth inhibition was a T-cell-mediated phenomenon. Besides the locoregional tumor growth inhibition, a systemic effect was recorded as the growth of a second tumor cell inoculum at the contralateral side was inhibited as well. Furthermore, those animals cured after PEG-IL-2 therapy developed specific immunity against the L10 tumor and this immunity could be transferred to naive animals by spleen cells. Immunohistological observations of the tumor site revealed a slight increase of helper and cytotoxic T cell subpopulations after PEG-IL-2 therapy. More pronounced, however, was the rise in number of eosinophilic granulocytes present in the stroma surrounding the tumor cells. Involvement of cytotoxic cells in the antitumor effects of PEG-IL-2 could not be demonstrated: regional lymph node cells and spleen cells obtained immediately after therapy (day 15) or on day 21 showed no cytotoxic activity in vitro against L10, K562, Daudi and line 1 (L1) target cells. In conclusion, locoregional therapy with PEG-IL-2 induced a a systemic T-cell-mediated antitumor response. As no cytotoxic T cell activity was measured, however, the underlying mechanism is most likely a T-helper response. Eosinophils at the tumor site may be tumoricidal but further experiments must reveal the role of these cells in the PEG-IL-2-induced tumor regression.
Laboratory for Pathology, National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands.
L T
LT
Balemans
V
V
Mattijssen
P A
PA
Steerenberg
B E
BE
Van Driel
P H
PH
De Mulder
W
W
Den Otter
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D015816:Cell Adhesion Molecules, Neuronal / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D005355:Fibrosis / Q000188:drug therapy; D006098:Granulocytes / Q000187:drug effects; D006168:Guinea Pigs; D007111:Immunity, Cellular; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive; D015552:Injections, Intralesional; D007272:Injections, Intralymphatic; D007376:Interleukin-2 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D039841:Leukocyte L1 Antigen Complex; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008207:Lymphatic Metastasis / Q000276:immunology / Q000517:prevention & control; D008297:Male; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols; D012074:Remission Induction; D013160:Splenic Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology
D000951:Antigens, Neoplasm; D015816:Cell Adhesion Molecules, Neuronal; D007376:Interleukin-2; D039841:Leukocyte L1 Antigen Complex; C067245:interleukin-2, polyethylene glycol-modified; D011092:Polyethylene Glycols