A novel tumor cell therapy using Th1 cells: The critical role of APC/Th1 cell-cell interaction for the initiation of antitumor immunity in vivo

Abstract

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The introduction of local help, which can overcome immunosuppression of tumor-bearing host, is essential for developing antigen-specific tumor immunotherapy. To introduce local help, we have investigated the adoptive tumor immunotherapy using Th1 cells or Th1 cytokine-conditioned bone marrow-derived dendritic cells (BMDC1). The adoptive transfer of OVA-specific Th1 cells (over 2x107) into tumor-bearing mice caused a complete regression of tumor mass of A20-OVA which were A20 B lymphoma cells transfected with OVA gene as a model tumor antigen. For successful Th1-cell therapy, host CD8+T cells were essential in addition to Th1 cells. Thus, Th1/Tc1 circuit appears to be important for complete rejection of tumor by Th1 cell therapy. To induce Th1-dominant antitumor immunity in A20-OVA-bearing mice, we also tried to apply OVA-pulsed BMDC1, which were preferable for inducing antigen-specific Th1 and Tc1 cells, to adoptive tumor immunotherapy. Vaccination of A20-OVA-bearing mice with intradermal injection of inactivated A20-OVA, OVA pulsed-BMDC1 or Th1 cells (5x106) alone showed no significant antitumor effect in vivo. However, combined vaccination therapy with OVA-pulsed BMDC1, A20-OVA and Th1 cells caused a complete regression of tumor mass. Thus, Th1 cells were demonstrated to augment BMDC1-based tumor vaccination therapy in vivo. Finally, we have succeeded to cure mice bearing with MHC class II-negative EG-7 tumor cells using Th1-cell therapy. Using this model, we demonstrated that APC/Th1 cell-cell interaction and Th1 cell expansion in draininig lymph node is essential for the induction of tetramer-positive tumor specific CTL and complete regression of tumor. We also succeeded in generation of tumor-specific human Th1 cells. Therefore, Th1-cell therapy will provide a new strategy for tumor cell therapy in future.