Tumor-specific cytokine release by donor T cells induces an effective hostanti-tumor response through recruitment of host naive antigen presenting cells

We recently reported that tumor eradication induced by immunotherapy (IT) i n a congenic mouse model using tumor infiltrating lymphocytes (TIL) + recom binant interleukin-2 (rlL-2) is dependent on recruitment of naive host immu ne cells at the tumor sites. The recruitment of host immune cells was induc ed mainly through a local secretion of interferon-gamma (IFN-gamma) produce d by donor T cells. We now further investigated how a non-specific inflamma tory response progresses to a host T-cell-mediated tumor-specific response. In crossover experiments using MCA-105 and MCA-205 sarcoma tumors, pulmona ry metastatic disease was eradicated only in mice treated with tumor-matche d TIL + rlL-2. In vitro, TIL stimulated with the tumor of origin secreted r elatively high levels of IFN-gamma and granulocyte-macrophage colony stimul ating factor (GM-CSF) compared to ill stimulated with mismatched tumor cell s. In lungs of tumor-bearing mice treated with matched TIL + rlL-2, signifi cant increases in the percentages of IFN-gamma, GM-CSF and tumor necrosis f actor-alpha (TNF-alpha) positive cells were detected, as well as of macroph ages, natural killer (NK) cells and dendritic cells. Depletion of macrophag es or NK cells did not inhibit the efficacy. In contrast, depletion of dend ritic cells partially inhibited the efficacy of the treatment. Combined dep letion of dendritic cells and macrophages abrogated more than 80% of the ef ficacy. Our data suggest that successful IT may require 3 steps: (I) releas e of inflammatory cytokines by donor TIL after restimulation by tumor cells ; (2) infiltration of host immune cells in response to local cytokine produ ction; and (3) activation of tumor-specific host immune cells by dendritic cells and to a lesser extent by macrophages. (C) 1999 Wiley-Liss, Inc.