Interleukin-15 effectively potentiates the in vitro tumor-specific activity and proliferation of peripheral blood γδT cells isolated from glioblastoma patients

gamma delta T cells play a regulatory role in both primary and metastatic tumor growth in humans. The mechanisms responsible for the activation and proliferation of circulating gamma delta T cells should be fully understood prior to their adoptive transfer to cancer patients. We have examined in vitro functional effects of interleukin-15 (IL-15) on highly purified gamma delta T cells isolated from glioblastoma patients, gamma delta T cells constitutively express the heterotrimeric IL-2 receptor (IL-2R) alpha beta gamma, but the levels of IL-2R beta or gamma expression were not increased by incubation with saturating amounts of IL-15. IL-15 was shown to induce a maximal gamma delta T cell proliferation, although at much higher concentrations (at least 2000 U/ml) than IL-2 (100 U/ml). Submaximal concentrations of IL-15 plus low concentrations of IL-2 produced an additive proliferative response. In contrast to the IL-2-induced response, this activity was completely or partially abrogated by anti-IL-2R beta, or anti-IL-2R gamma antibodies, but not by anti-IL-2R alpha antibodies. Incubation of gamma delta T cells in the presence of IL-15 resulted not only in the appearance of NK and LAK activity, but also in specific autologous tumor cell killing activity, an additive effect being seen with IL-15 and TL-2. This IL-15-induced tumor-specific activity could be significantly blocked by anti-IL-2R gamma and anti-IL-2R-beta mAb, but not by anti-IL-2R alpha mAb. Thus, in contrast to IL-2, IL-15 activates tumor-specific gamma delta T cells through the components of IL-2R beta and IL-2R gamma, but not IL-2R alpha. These enhanced in vitro tumor-specific and proliferative responses of gamma delta T cells seen with IL-15 suggest a rational adjuvant imunotherapeutic use of gamma delta T cells in cancer patients.