Immune events associated with the cure of established tumors and spontaneous metastases by local and systemic interleukin 12

The antitumor activity of recombinant murine interleukin-12 (rIL-12) is doc umented by a large set of data from numerous mouse models. Because the cell ular and molecular mechanisms by which rIL-12 impairs tumor growth are stil l not fully defined, we compared the effects of local and systemic rIL-12 a dministration in mice harboring an invasive 7-day-old moderately differenti ated and spontaneously metastasizing mammary adenocarcinoma (TSA). Whereas the immune events elicited via the tao routes of rIL-12 administration seem to be the same, systemic rIL-12 is markedly more effective; tumor destruct ion is dependent on a prompt antitumor response resulting from the cooperat ion of several subsets of reactive cells, The reactions that seem to play a key role are: ia) indirect inhibition of angiogenesis by secondary cytokin es (mainly IFN-gamma) and third-level chemokines (inducible protein 10 and monokine induced by IFN-gamma); (b) systemic activation of leukocyte subset s capable of producing proinflammatory cytokines, CTLs, and antitumor antib odies; and (c) destruction of tumor vessels by polymorphonuclear cells. The markedly higher efficacy of systemic rIL-12 seems to rest on its ability t o recruit these systemic reactions more quickly and efficiently than local rIL-12.