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-Dependent CXC Chemokines in Syngeneic Mice1
* Dipartimento di Oncologia e Neuroscienze, Università di Chieti, Chieti, Italy;
Istituto Nazionale per la Ricerca sul Cancro, and
Istituto Giannina Gaslini, Genoa, Italy; and
Istituto Nazionale Tumori, Milan, Italy
IL-21 is an immune-stimulatory four 
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-, IFN-
, and endothelial adhesion molecules ICAM-1 and VCAM-1. At day 7, CD8+ and CD4+ T cells increased together with IFN-, and the CXC chemokines IFN--inducible protein 10, monokine induced by IFN-, and IFN-inducible T cell -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--deficient mice, TS/A-IL-21 cells formed tumors that regressed in only 29% of animals, indicating a role for IFN- in IL-21-mediated antitumor response, but also the existence of IFN--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.
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