Expression of NK-associated receptors on cytotoxic T cells from melanoma patients: a two-edged sword?

Abstract

The coexistence of tumor progression with a tumor-specific immune response constitutes a major paradox of tumor immunity. During the last decade, the presence of cytotoxic T lymphocytes (CTLs) recognising melanoma-associated antigens has been unequivocally demonstrated in numerous different in vivo and in vitro models. However, most often these melanoma-specific T lymphocytes do not control tumor growth. Several mechanisms that involve changes in melanoma phenotype and/or in T-cell differentiation and function could explain the inability of the immune response to control melanoma. In the last few years it has been demonstrated that cellular cytotoxicity is the result of a balance between activating signals triggered by the TCR and costimulatory molecules and inhibitory signals triggered by inhibitory receptors expressed by the CTL. Because the final outcome of the immune response against melanoma depends on the balance between activating and inhibitory signals, the expression de novo on melanoma cells of ligands for inhibitory NKRs and the down-regulation of costimulatory molecules may favor the escape of tumor cells from immunosurveillance. In this paper we review how altered expression of molecules required for T-cell costimulation could result in impaired lysis of melanoma. The modulation of antimelanoma T-cell responses by a group of receptors originally described on NK cells (NK-associated receptors) but which are now known also to be expressed on a subset of cytolytic effector cells is reviewed. We hypothesize that the expression of ligands for NKRs on melanoma cells may contribute to T-cell-mediated immune responses against melanoma either enhancing or inhibiting activation and differentiation to effector cells. Blocking inhibitory receptors or increasing activating receptors could result in new strategies to improve T-cell-mediated rejection of melanoma.

Fig. 1

Immune responses against melanoma. Different cell types participate in the rejection of tumor cells leading to tumor immunity. A potential consequence of tumor immunity is autoimmunity. Immune intervention can enhance tumor immunity and overcome the immune tolerance status mediated by several escape mechanisms

Fig. 2A,B

Inhibitory and activating NKRs. Expression and function of human NKRs on cytotoxic cells and their potential ligands on melanoma cells. A HLA class I–specific receptors. B Non-HLA-specific receptors

Fig. 3

Inhibitory/activating balance. Different receptors participate in the immune response against melanoma mediated by CTLs. Positive signals mediated by TCR and costimulatory molecules may be enhanced by the expression of activating NKRs on CTLs and their ligands on melanoma. By contrast, inhibitory signals triggered by inhibitory NKRs after interaction with their ligands will allow melanoma escape from immunosurveillance