Biomarkers of suppressed natural killer (NK) cell function in metastatic melanoma: Decreased NKG2D and increased CD158a receptors on CD3–CD16+ NK cells

Abstract

In metastatic melanoma (MM) patients we evaluated natural killer (NK)-cell activity, distribution of several NK receptors and their correlation with NK function. Peripheral blood lymphocytes (PBL) of MM patients and controls were analysed for NK activity and expression of activating NKG2D, CD161 and KIR, CD158a and CD158b receptors on CD3-CD16+ NK cells. MM patients not only had significantly decreased NK activity and NK-cell interferon (IFN)-gamma production, a redistribution of NK-cell subsets with an increase in CD16(dim) and a reduction in CD16(bright) NK subsets. There was a decreased CD161 and NKG2D and an increased CD158a NK-cell expression in MM patients, with a positive correlation between NKG2D expression and NK cytotoxicity and an inverse correlation between CD158b expression and NK-cell cytotoxicity in patients. Furthermore, patients' CD3-CD16(bright) NK subset showed lower expression of CD161 and CD158a. Therefore, NKG2D, CD158a and CD158b expression in MM patients may represent several clinically useful 'biomarkers' of suppressed NK function.

Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells

“…Previous studies have shown no differences in NKG2D expression between peripheral blood mononuclear cells (PBMCs) and LN NK cells in melanoma patients and healthy individuals. [33][34][35][36] However, these studies did not examine the NKG2D expression in tumor infiltrating NK cells. We observed significantly lower NKG2D expression in the intratumoral NK cells, but no difference in the splenic population, between naive and tumorbearing mice.…”

The Role of Activating and Inhibitory NK Cell Receptors in Antitumor Immune Response

“…Other studies in patients with metastatic melanoma, as well as in NSCLC and breast cancer, show an increase in the expression of CD158a and CD158b inhibitory KIR receptors on NK cells [33,[49][50][51] that in melanoma negatively correlates with NK cell cytotoxicity [33]. In this sense, as inhibitory KIR play prominent roles in regulating NK cell activation therapeutic strategies designed to diminish KIR function that may be able to potentiate NK cell activity in treating patients with malignancies.…”

“…Moreover, as CD16 deines the two functionally diferent NK cell subsets, its decreased expression inluences the ratio of these subsets, leading to the loss CD16 bright cytotoxic subset, a inding that has been detected in numerous malignancies such as breast cancer, MM, and melanoma [6,33].…”

“…In support of the inhibitory function of NKR-P1A, it has been shown that its cytoplasmic tail contains tyrosine residue in an atypical motive (AxYxxL) that may function as a weak ITIM [63,64]. There are some reports of decreased expression and cytokine-mediated upregulation of NKR-P1A/CD161 in metastatic melanoma and MM [29,33,58].…”

“…This efect is more pronounced for K562 tumor cells as they highly express MICA/B ligands speciic for NKG2D receptors [31], while for FemX tumor cell line so far no data exist regarding the expression of MICA/B ligands, although it can be assumed that, as most tumor cells, this cell line expresses some level of these stress-induced ligands. The importance of NKG2D receptor in NK cell cytotoxic function underlies a signiicant positive correlation of its expression with NK cytotoxicity in healthy individuals, as well as in melanoma patients, in spite of diferent levels of expression [32][33][34].…”