IFN-γspielt eine entscheidende Rolle bei aktiv-spezifischer Tumortherapie, jedoch nicht bei Tumorregression nach adoptiven T-Zell Transfer

Abstract

Introduction: The adoptive transfer of tumor-specific T cells from tumor vaccine draining lymph nodes (TVDLN) can result in complete regression of solid tumor. The tumorspecific release of IFN-γ, a type 1 cytokine, has been associated with therapeutic efficacy of adoptively transferred lymphocytes. The goal of the study was to evaluate the role of IFN-γ in adoptive immunotherapy and active-specific immunotherapy in a B16BL6-D5 (D5) murine melanoma model. Methods: Wild-type (wt) and IFN-γ k/o (GKO) mice were vaccinated s.c. with 1 x 10 7 irradiated D5-G6 cells, a stable GM-CSF transfected subclone of D5 to induce active-specific immunity. The mice were rechallenged 14 days after vaccination with 2 x 10 4 D5 and the tumor growth determined by measurement of two perpendicular diameters using a caliper. To generate tumor-specific T cells from TVDLN, wt and GKO mice were vaccinated s.c. with 1 x 10 6 D5-G6. TVDLN cells were activated in vitro with anti-CD3, expanded with IL-2 and adoptively transferred into wt, GKO and IFN-γ receptor k/o (GRKO) mice with established pulmonary metastases of D5 tumor. The number of pulmonary metastases was determined 10 days after adoptive transfer. The tumorspecific cytokine release of the effector T cells was determined in vitro by ELISA; tumorspecific cytotoxicity was determined in a 6-h 51Cr release assay. Results: Induction of active- specific immunity by D5-G6 a GM-CSF secreting tumor vaccine induces significant tumor protection in wt ( p < 0.01), but not in GKO mice. In contrast, adoptively transferred D5-G6 TVDLN cells from wt and GKO mice induced significant tumor regression in wt, GKO and GRKO mice (p < 0.01), cured 100% of GKO mice and induced long-term antitumor immunity. One hundred percent of the cured GKO mice that survived longer than 100 days rejected D5 after a s.c. rechallenge with native tumor. Seventy-five percent of the wt and 40% of the GKO mice developed vitiligo after rechallenge. CD8+ wt and GKO D5- G6 TVDLN cells are tumor-specifically cytotoxic for D5. Conclusion; The results show an interesting dichotomy in the requirement for IFN-γ: Antitumor immunity induced by active- specific immunotherapy (vaccination) required IFN-γ while adoptive immunotherapy did not.