IL-21 induces tumor rejection by specific CTL and IFN-gamma-dependent CXC chemokines in syngeneic mice.
IL-21 is an immune-stimulatory four alpha helix cytokine produced by activated T cells. To study the in vivo antitumor activities of IL-21, TS/A murine mammary adenocarcinoma cells were genetically modified to secrete IL-21 (TS/A-IL-21). These cells developed small tumors that were subsequently rejected by 90% of s.c. injected syngeneic mice. Five days after injection, TS/A-IL-21 tumors showed numerous infiltrating granulocytes, NK cells, and to a lesser extent CD8(+) T cells, along with the expression of TNF-alpha, IFN-gamma, and endothelial adhesion molecules ICAM-1 and VCAM-1. At day 7, CD8(+) and CD4(+) T cells increased together with IFN-gamma, and the CXC chemokines IFN-gamma-inducible protein 10, monokine induced by IFN-gamma, and IFN-inducible T cell alpha-chemoattractant. The TS/A-IL-21 tumor displayed a disrupted vascular network with abortive sprouting and signs of endothelial cell damage. In vivo depletion experiments by specific Abs showed that rejection of TS/A-IL-21 cells required CD8(+) T lymphocytes and granulocytes. When injected in IFN-gamma-deficient mice, TS/A-IL-21 cells formed tumors that regressed in only 29% of animals, indicating a role for IFN-gamma in IL-21-mediated antitumor response, but also the existence of IFN-gamma-independent effects. Most immunocompetent mice rejecting TS/A-IL-21 cells developed protective immunity against TS/A-pc (75%) and against the antigenically related C26 colon carcinoma cells (61%), as indicated by rechallenge experiments. A specific CTL response against the gp70-env protein of an endogenous murine retrovirus coexpressed by TS/A and C26 cells was detected in mice rejecting TS/A-IL-21 cells. These data suggest that IL-21 represents a suitable adjuvant in inducing specific CTL responses.
Di Carlo
Emma
E
Dipartimento di Oncologia e Neuroscienze, Università di Chieti, Chieti, Italy.
Comes
Alberto
A
Orengo
Anna Maria
AM
Rosso
Ombretta
O
Meazza
Raffaella
R
Musiani
Piero
P
Colombo
Mario P
MP
Ferrini
Silvano
S
D000230:Adenocarcinoma / Q000098:blood supply / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D000380:Agranulocytosis / Q000276:immunology; D020533:Angiogenesis Inhibitors / Q000502:physiology; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000502:physiology*; D005260:Female; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology*; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007378:Interleukins / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008231:Lymphopenia / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009368:Neoplasm Transplantation / Q000276:immunology; D015202:Protein Engineering / Q000379:methods; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D000098546:Interleukin-21
D020533:Angiogenesis Inhibitors; D019496:Cancer Vaccines; D019743:Chemokines, CXC; D007378:Interleukins; D007371:Interferon-gamma; D000098546:Interleukin-21