Strong expression of the lymphoattractant C-X-C chemokine Mig is associated with heavy infiltration of T cells in human malignant melanoma

Abstract

Human malignant melanoma (MM) is a highly aggressive tumour which is particularly prone to specific local immune responses. To determine the microanatomical location and the species of chemokines possibly involved in the intricate control of cell migration and positioning of immune effector cells in primary and metastatic MM lesions, the expression of those chemokines with lymphocyte and/or macrophage chemoattractant properties was analysed by in situ hybridization. GROalpha (growth-related oncogene) and IL-8 (interleukin 8) were expressed at low levels by single melanoma cells, adjacent keratinocytes, and infiltrating leukocytes. In contrast, the lymphocyte-specific chemokine Mig (monokine induced by interferon-gamma) was strongly expressed by mononuclear cells (mainly macrophages) infiltrating the tumour margin in primary MM lesions, whereas expression was less intense in MM metastasis. IP-10 (interferon-gamma inducible protein 10) was expressed in the same loci at lower intensity. Marked infiltration of T cells was exclusively detected in those areas which exhibited strong Mig expression, whereas areas in the vicinity of tumour cells devoid of Mig expression were not infiltrated. In contrast to Mig, expression of MCP-1 (macrophage chemotactic protein-1) was weaker and mainly detected in lesional basal keratinocytes, occasionally at sites of macrophage infiltration, as well as in single melanoma cells. MIP-1alpha (macrophage inflammatory protein 1alpha) showed similar, albeit weaker expression compared with MCP-1. Other chemokines relevant for the recruitment of monocytes and lymphocytes, such as RANTES (regulated on activation, normal T cells expressed and secreted) and MIP-1beta, were barely detectable. In summary, the chemokine expression profiles support the notion that particularly in heavily infiltrated primary MM lesions, Mig and to a lesser extent IP-10 are important mediators of an IFN-gamma-dependent pathway. Due to their lymphoattractant properties and the known inhibitory effects on the tumour vasculature, both chemokines may be critical for the control of local melanoma tumour growth.