IFN-gamma-independent synergistic effects of IL-12 and IL-15 induce anti-tumor immune responses in syngeneic mice.
IL-15 and IL-12 display anti-tumor activity in different models and IFN-gamma has been reported as a secondary mediator of both IL-12 and IL-15 effects. TS/A murine adenocarcinoma cells were engineered to secrete IL-12, IL-15 or both cytokines. TS/A cells secreting IL-15 (TS/A-IL-15) displayed a reduced tumorigenicity (50%) when implanted subcutaneously in syngeneic mice, while both TS/A-IL-12 and TS/A-IL-12/IL-15 were rejected by 100% of animals. In contrast, TS/A-IL-15 and TS/A-IL-12 were tumorigenic in syngeneic IFN-gamma knockout mice (100% and >90% of take rate, respectively), but TS/A-IL-12/IL-15 were completely rejected by 90% of these mice. All IFN-gamma-deficient mice rejecting TS/A-IL-12/IL-15 developed protective immunity against wild-type TS/A, as indicated by re-challenge experiments. Immunohistochemical analysis of the TS/A-IL-12/IL-15 tumor rejection area in IFN-gamma-deficient mice showed a marked reactive cell infiltration constituted of CD8+ cells, granulocytes, NK cells, macrophages and dendritic cells associated with the expression of IL-1beta, TNF-alpha, GM-CSF, MCP-1 and MIP-2. In vivo depletion experiments showed that rejection of TS/A-IL-12/IL-15 cells required CD8+ T lymphocytes and also involved granulocytes, while CD4+ and NK cells played a minor role. These data show IFN-gamma-independent synergistic anti-tumor effects of IL-12 and IL-15, involving CD8+ cells and secondary chemokines and cytokines, such as TNF-alpha.
Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Alberto
A
Comes
Emma
E
Di Carlo
Piero
P
Musiani
Ombretta
O
Rosso
Raffaella
R
Meazza
Claudia
C
Chiodoni
Mario P
MP
Colombo
Silvano
S
Ferrini
D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015197:Carcinogenicity Tests; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006098:Granulocytes / Q000276:immunology; D007150:Immunohistochemistry / Q000379:methods; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology*; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D019409:Interleukin-15; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma