The distinct role of CD4(+) and CD8(+) T-cells during the anti-tumour effects of targeted superantigens

To target T-cells to the tumour area we created a recombinant protein of th e bacterial superantigen (SAg) Staphylococcal enterotoxin A (SEA) and the F ab-fragment of a tumour-reactive antibody. This antibody-targeted SAg immun otherapy therapy has been shown to be highly efficient, eliminating > 95% o f the pulmonary metastasis in mice carrying established melanoma micrometas tases. Earlier studies demonstrated that elimination of the C215-expressing B16-melanoma lung metastasis was dependent on interferon (IFN)-gamma relea se and expression of perforin. In the present study, therapeutic effector f unctions were analysed both locally at the tumour site and systemically in the spleen. In order to elucidate the role of each T-cell subset during Fab -SEA therapy, CD4 knock-out (KO) and CD8 KO mice were used. Tumour size red uction was statistically significant in Fab-SEA-based tumour therapy in bot h types of T-cell-deficient mice compared to wild-type mice. CD4 KO mice di splayed a drastic reduction in the number of tumour-infiltrating macrophage s and CD8(+) T-cells. Therapy-induced accumulation of perforin-containing c ells at the tumour site was significantly impaired in CD8 KO mice, and marg inally in CD4 KO mice. Moreover, CD4 KO mice failed to produce substantial amounts of the tumour suppressive cytokine IFN-gamma, This is in sharp cont rast to normal mice where a massive local release was recorded. CD8 KO mice displayed a spontaneous production of interleukin (IL)-4 and IL-10 locally in the tumour. Neither normal nor CD4 KO mice produced detectable levels o f these Th-2-associated cytokines. The high level of IL-10 was demonstrated to inhibit Fab-SEA tumour therapy, since the therapeutic efficacy was sign ificantly higher in IL-10 KO mice. These results illustrate the importance of a finely tuned cellular collaboration to regulate the Various phases of an efficient anti-tumour immune response. (C) 1999 Cancer Research Campaign .