STIMULATION OF TUMOR-DRAINING LYMPH-NODE CELLS WITH SUPERANTIGENIC STAPHYLOCOCCAL TOXINS LEADS TO THE GENERATION OF TUMOR-SPECIFIC EFFECTORT-CELLS

In animal studies, lymph nodes (LN) draining progressive tumors contai n immunologically sensitized but functionally deficient T cells. These preeffector cells can differentiate into mature effector cells on sti mulation in vitro with anti-CD3 and IL-2. However, anti-CD3 react with all T cells and the activated cell population expressed a broad but n ormal distribution of Vbeta phenotypes. In this study, we examined the feasibility of using bacterial superantigens to stimulate tumor-drain ing LN cells. Because of their TCR Vbeta restriction, superantigen act ivation may afford a means to identify T cell subsets that are importa nt in the antitumor immune response. Stimulation of draining LN cells with staphylococcal enterotoxins A (SEA) or B (SEB) followed by cultur e in IL-2 resulted in selective activation and expansion of Vbeta3 and . Vbeta11 or Vbeta3 and Vbeta8 T cells, respectively. However, in adop tive immunotherapy, SEB- but not SEA-activated cells mediated the regr ession of established pulmonary metastases. To define the relative ant itumor effects of Vbeta3 and Vbeta8 T cells, SEB-activated cells were depleted of either Vbeta3 or Vbeta8 T cells with mAb and magnetic bead s. The antitumor effects were demonstratably diminished after Vbeta8 c ell depletion but enhanced after Vbeta3 cell depletion. Using antigeni cally distinct MCA 205 and 207 sarcomas, tumor regression mediated by the activated cells was found to be immunologically specific for the t umor that stimulated the draining LN. Furthermore, the SEB-activated c ells were virtually all T cells consisting of approximately equal prop ortions of CD4+ and CD8+ cells and the collaboration of the two T cell subsets was required for in vivo antitumor effects. However, the help er function of CD4+ cells could be facilitated by the administration o f exogenous IL-2. Despite their in vivo antitumor reactivity, SEB-acti vated cells did not exhibit tumor cytotoxicity in the 4-h C-51r releas e assay. However, they secreted IFN-gamma on specific stimulation with tumor cells. Taken together, these results provide for the first time clear evidence of the functional significance of superantigen interac tions with immunologically committed T cells and suggest a preferentia l Vbeta use that might be associated with the T cell immune response t o progressively growing tumors.