title: Systemic administration of cellular IL-10 induces an effective, specific, and long-lived immune response against established tumors in mice.
abstract: Cellular IL-10 (cIL-10), the collective term for human and murine IL-10, has both stimulatory and inhibitory effects on diverse cell types, including costimulation of T cell proliferation, chemoattraction of CD8+ T cells, and stimulation of lymphokine-activated killer cell activity. Human IL-10 (hIL-10) differs from its EBV homolog viral IL-10 (vIL-10) by only 16% at the amino acid level; however, vIL-10 shares with cIL-10 predominantly inhibitory effects, such as macrophage deactivation. We administered cIL-10 systemically to mice bearing established (day 7) sarcomas, melanomas, or colorectal carcinomas. At high doses (20 to 60 micrograms/day x 7 days), cIL-10 induced rejection of tumors, delaying tumor outgrowth or resulting in complete cure. Sublethal irradiation (500 rad) of mice prior to tumor inoculation abrogated the IL-10 effect. Cured mice were immune to subsequent rechallenge with 10-fold higher inoculation with the same, but not a different, tumor. IL-12 also has potent antitumor activity and interacts with IL-10 in both complementary and antagonistic ways; co-administration of both cytokines resulted in additive antitumor activity. To compare cIL-10 vs vIL-10 effects in vivo, we engineered CL8-1 melanoma transfectants bearing the vIL-10 or the murine IL-10 (mIL-10) gene. Local secretion of mIL-10 induced rejection of tumors, while vIL-10 resulted in accelerated outgrowth. Subsequent systemic administration of cIL-10 to mice bearing vIL-10-transduced tumors completely reversed the local suppressive effects, leading to rejection, suggesting distinct pathways for cIL-10 and vIL-10 effects. That cIL-10 can stimulate the acquisition of an effective, specific, and long-lived antitumor immune response in murine models and can reverse the local immunosuppressive effects of vIL-10 indicates a potential role for cIL-10 administration in the biologic therapy of cancer and suggests a broader interpretation of IL-10 biology.
authors.affiliation: Department of Molecular Genetics and Biochemistry, School of Medicine, University of Pittsburgh, PA 15261, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Berman
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: H
authors.initials: H
authors.lastname: Tahara
authors.forename: P D
authors.initials: PD
authors.lastname: Robbins
authors.forename: S K
authors.initials: SK
authors.lastname: Narula
authors.forename: M T
authors.initials: MT
authors.lastname: Lotze
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000628:therapy*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D003110:Colonic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods; D007271:Injections, Intradermal; D016753:Interleukin-10 / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018664:Interleukin-12 / Q000627:therapeutic use; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D012513:Sarcoma, Experimental / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D013154:Spleen / Q000166:cytology
chemical_list: D000276:Adjuvants, Immunologic; D011994:Recombinant Proteins; D016753:Interleukin-10; D018664:Interleukin-12