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.

CD8+ CD28− and CD8+ CD57+ T cells and their role in health and disease

“…Expression of NK cell receptors (NKRs) was initially identified on NK cells, later it was shown that functionally active NKRs are expressed on the surface of T‐cell subsets and may regulate their functional activity 93–95 . The great majority of T cells expressing NKRs are included particularly within the CD8 + CD28 − (CD8 + CD57 + ) T‐cell population 16,72,96 …”

Age-Dependent Association between Low Frequency of CD27/CD28 Expression on pp65 CD8+T Cells and Cytomegalovirus Replication after Transplantation

“…Ϫ effector cells which might show characteristics of senescent cells (17,44) (20,35), cancer (6,7,11,30,40), and other latent viral infections, such as infection with human immunodeficiency virus (HIV) or Epstein-Barr virus (3,48). Therefore, even though all patients with viral replication included in our study had a high percentage of CD27 Ϫ or CD28 Ϫ cells in the HCMV-specific T-cell population, this subpopulation might have distinct functions, depending on the length of contact with the virus.…”

The Tumor Microenvironment: A Pitch for Multiple Players

“…In this regard, melanoma cells have been shown to down-regulate the MHC-I surface expression, thus bypassing the interaction with CTL via TCR (Mempel and Bauer, 2009). Of note, some reports demonstrated that induction of co-stimulatory molecule expression in human melanoma cell surface led to stimulation of CTL activity by Natural killer (NK) cells (Tarazona et al, 2004). …”