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

Abstract

We recently reported that tumor eradication induced by immunotherapy (IT) in a congenic mouse model using tumor infiltrating lymphocytes (TIL) + recombinant interleukin-2 (rIL-2) is dependent on recruitment of naive host immune cells at the tumor sites. The recruitment of host immune cells was induced mainly through a local secretion of interferon-gamma (IFN-gamma) produced by donor T cells. We now further investigated how a non-specific inflammatory response progresses to a host T-cell-mediated tumor-specific response. In cross-over experiments using MCA-105 and MCA-205 sarcoma tumors, pulmonary metastatic disease was eradicated only in mice treated with tumor-matched TIL + rIL-2. In vitro, TIL stimulated with the tumor of origin secreted relatively high levels of IFN-gamma and granulocyte-macrophage colony stimulating factor (GM-CSF) compared to TIL stimulated with mismatched tumor cells. In lungs of tumor-bearing mice treated with matched TIL + rIL-2, significant increases in the percentages of IFN-gamma, GM-CSF and tumor necrosis factor-alpha (TNF-alpha) positive cells were detected, as well as of macrophages, natural killer (NK) cells and dendritic cells. Depletion of macrophages or NK cells did not inhibit the efficacy. In contrast, depletion of dendritic cells partially inhibited the efficacy of the treatment. Combined depletion of dendritic cells and macrophages abrogated more than 80% of the efficacy. Our data suggest that successful IT may require 3 steps: (1) release of inflammatory cytokines by donor TIL after restimulation by tumor cells; (2) infiltration of host immune cells in response to local cytokine production; and (3) activation of tumor-specific host immune cells by dendritic cells and to a lesser extent by macrophages.