IL-2 intratumoral immunotherapy enhances CD8+ T cells that mediate destruction of tumor cells and tumor-associated vasculature: a novel mechanism for IL-2.
Therapeutic use of IL-2 can generate antitumor immunity; however, a variety of different mechanisms have been reported. We injected IL-2 intratumorally (i.t.) at different stages of growth, using our unique murine model of mesothelioma (AE17; and AE17 transfected with secretory OVA (AE17-sOVA)), and systematically analyzed real-time events as they occurred in vivo. The majority of mice with small tumors when treatment commenced displayed complete tumor regression, remained tumor free for >2 mo, and survived rechallenge with AE17 tumor cells. However, mice with large tumors at the start of treatment failed to respond. Timing experiments showed that IL-2-mediated responses were dependent upon tumor size, not on the duration of disease. Although i.t. IL-2 did not alter tumor Ag presentation in draining lymph nodes, it did enhance a previously primed, endogenous, tumor-specific in vivo CTL response that coincided with regressing tumors. Both CD4(+) and CD8(+) cells were required for IL-2-mediated tumor eradication, because IL-2 therapy failed in CD4(+)-depleted, CD8(+)-depleted, and both CD4(+)- and CD8(+)-depleted C57BL/6J animals. Tumor-infiltrating CD8(+) T cells, but not CD4(+) T cells, increased in association with a marked reduction in tumor-associated vascularity. Destruction of blood vessels required CD8(+) T cells, because this did not occur in nude mice or in CD8(+)-depleted C57BL/6J mice. These results show that repeated doses of i.t. (but not systemic) IL-2 mediates tumor regression via an enhanced endogenous tumor-specific CTL response concomitant with reduced vasculature, thereby demonstrating a novel mechanism for IL-2 activity.
Jackaman
Connie
C
School of Medicine and Pharmacology, University of Western Australia.
Bundell
Christine S
CS
Kinnear
Beverley F
BF
Smith
Alison M
AM
Filion
Pierre
P
van Hagen
Deborah
D
Robinson
Bruce W S
BW
Nelson
Delia J
DJ
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D017951:Antigen Presentation; D015703:Antigens, CD / Q000096:biosynthesis; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D016923:Cell Death / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004527:Egg Proteins / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D016056:Immunodominant Epitopes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016233:Immunotherapy, Active / Q000379:methods*; D015552:Injections, Intralesional; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use*; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008654:Mesothelioma / Q000098:blood supply / Q000401:mortality / Q000628:therapy* / Q000648:ultrastructure; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D009336:Necrosis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D010047:Ovalbumin / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics; D010446:Peptide Fragments; D015996:Survival Rate; D016176:T-Lymphocyte Subsets / Q000276:immunology
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D004527:Egg Proteins; D006131:Growth Inhibitors; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D007376:Interleukin-2; D008562:Membrane Glycoproteins; C110366:OVA-8; D010446:Peptide Fragments; D010047:Ovalbumin