Inhibitory effects of alloimmune T cells on the generation of cytolytic responses of lymphokine-activated killer cells

Not all cancer-bearing hosts respond to interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cell immunotherapy. We wished to determine if modification of the host could change the immunotherapeutic effects. Alloimmunization of the host was used to study the suppression observed when LAK cells were generated in the presence of cytotoxic T lymphocytes (CTL). If C57BL/6 (BL/6, H-2^b) mice were given P815 (H-2^d) tumor prior to syngeneic tumor challenge, the immunotherapeutic effects of IL-2 were lost. Cells taken from mixed lymphocyte culture and incubated 3 days in IL-2 showed a reduced capability of generating LAK. However, their cytotoxicity toward an alloimmunogeneic target was markedly increased by 3 days of incubation in IL-2. In mixing experiments alloimmune cells from in vitro culture were markedly inhibitory to normal splenocytes in the generation of LAK cell cytotoxicity; they also interfered with the maintenance of LAK cell cytotoxicity. A T cell was responsible for the suppressive effects on LAK generation because suppression was abrogated by treatment of alloimmune cells with anti-T serum plus complement. The cytotoxic T cell did not lyse the LAK cell. If IL-2 was serially diluted and incubated with CTLs, the IL-2 titer was substantially reduced by 72 h incubation. If supernatants from CTLs were added to serially diluted IL-2, the IL-2 titer increased; this suggested that a soluble suppressor factor produced by CTLs did not cause the diminished IL-2 plus LAK effects. These in vitro experiments suggest that CTLs compete with normal lymphocytes or LAK cells for IL-2 and thereby suppress LAK cell responses. These studies are important in attempting to elucidate the role the host's immune system may play in IL-2 plus LAK immunotherapy of cancer or infectious disease processes.