Figure 8.

Schematic representation of the hypothesized chain of events that follows high-dose IL-2 administration deduced by serial gene profiling of PBMC and of FNA of melanoma metastases. Administration of IL-2 first affects leukocytes in the peripheral circulation where the IL-2 receptor is immediately upregulated on key effector mononuclear cells (lymphocytes, monocytes and NK cells). Lymphocytes and NK cells directly respond to IL-2 by releasing IFN-γ, whereas monocytes upregulate CD64, a typical marker of phagocytic activity, the receptor for the inflammatory cytokine IL-1RI, and most probably begin to release IL-1α/β in a stimulatory autocrine feedback loop. Further amplification of the biological effects of IL-1 is achieved by the ability of IL-1 to upregulate receptor expression for itself, IL-2R, IFNγR and GM-CSF/IL-3/IL-5R. The circulating pro-inflammatory cytokines IL-6 and IFN-γ further increase monocyte activation by triggering the release of MCP-3 and MCP-1 and/or inducing monocyte mobilization to the tumor microenvironment. Macrophages expressing IL-1RI and IFNγR that reach the tumor microenvironment, along with resident macrophages, release additional chemokines and cytokines (MCP-3, MIP-1α and β, MIG, PARC/MCP-4, IL-8), affecting the trafficking and/or activation of monocytes themselves, lymphocytes/NK cells, dendritic cells and fibroblasts, which in turn can release inflammatory factors. Migration to the tumor microenvironment is also reflected by the active transcription of molecules involved in adhesion of mononuclear cells (CD62L selectin) to vascular endothelial cells (V-CAM). In addition, upregulation of mRNA expression for the cytolytic granule proteins calgranulin/grancalcin and NKG5 underlies the induction of a cytotoxic response by monocytes/macrophages and NK cells, respectively. The net effect of the IL-2-induced inflammatory cascade in the tumor microenvironment is the dominant expression of IFN-γ-dependent genes (MHC class II, HSP70, MxA, MxB) and/or IFN-γ regulatory genes (IRF-1, IF1616, GBP1 interferon inducible, IEF protein).