TRANSFECTION OF TRANSFORMING GROWTH-FACTOR-BETA PRODUCING TUMOR EMT6 WITH INTERLEUKIN-2 ELICITS TUMOR REJECTION AND TUMOR REACTIVE CYTOTOXIC T-LYMPHOCYTES

One mechanism by which potentially immunogenic tumors evade the immune response is production of immunosuppressive factors. The murine mamma ry sarcoma EMT6 has previously been demonstrated to inhibit the prolif eration of B-cells, suggesting that this tumor produces immunosuppress ive factors. Here, we show that supernatant from EMT6 inhibits the dev elopment of cytotoxic T-lymphocytes (CTLs) and that this inhibition ca n be reversed by addition of recombinant interleukin (IL)-2. Furthermo re, we show that EMT6 produces high levels of the immunosuppressant fa ctor transforming growth factor (TGF)-beta. To determine if the T-cell growth factor IL-2 within the tumor microenvironment could reverse th e immunosuppressive effect of EMT6, we transfected EMT6 with an expres sion vector containing the cDNA for murine IL-2 under the control of t he p-actin promoter. These transfectants produce significant levels of IL-2 (26 U/ml). EMT6/IL-2 is rejected by mice at 100-fold higher chal lenge than are parental cells or control transfectants (neomycin resis tance only). Thy-1-expressing cells purified from EMT6/IL-2 tumors sho w greater cytotoxicity against the parental EMT6 cells than do those f rom the control transfectant. Thus, IL-2 can reverse the effects of TG F-beta on development and/or proliferation of CTL reactive with EMT6, allowing the establishment of mature effecters in vivo. This has signi ficant implications for the development of CTL and immunotherapy for i mmunosuppressive tumors.