Abstract
Melanomas are aggressive skin tumors characterized by high metastatic potential. Our previous results indicate that Natural Killer (NK) cells may control growth of melanoma. The main defect of blood NK cells was a decreased expression of activating NCR1/NKp46 receptor and a positive correlation of NKp46 expression with disease outcome in stage IV melanoma patients was found. In addition, in stage III melanoma patients, we identified a new subset of mature NK cells in macro-metastatic Lymph nodes (LN). In the present studies, we evaluated the numbers of NK cells infiltrating primary cutaneous melanoma and analyzed immune cell subsets in a series of sentinel lymph nodes (SLN). First, we show that NKp46+ NK cells infiltrate primary cutaneous melanoma. Their numbers were related to age of patients and not to Breslow thickness. Then, a series of patients with tumor-negative or -positive sentinel lymph nodes matched for Breslow thickness of the cutaneous melanoma was constituted. We investigated the distribution of macrophages (CD68), endothelial cells, NK cells, granzyme B positive (GrzB+) cells and CD8+ T cells in the SLN. Negative SLN (SLN-) were characterized by frequent adipose involution and follicular hyperplasia compared to positive SLN (SLN+). High densities of macrophages and endothelial cells (CD34), prominent in SLN+, infiltrate SLN and may reflect a tumor favorable microenvironment. Few but similar numbers of NK and GrzB+ cells were found in SLN- and SLN+: NK cells and GrzB+ cells were not correlated. Numerous CD8+ T cells infiltrated SLN with a trend for higher numbers in SLN-. Moreover, CD8+ T cells and GrzB+ cells correlated in SLN- not in SLN+. We also observed that the numbers of CD8+ T cells negatively correlated with endothelial cells in SLN-. The numbers of NK, GrzB+ or CD8+ T cells had no significant impact on overall survival. However, we found that the 5 year-relapse rate was higher in SLN with higher numbers of NK cells.
Highlights
Melanoma is an aggressive skin tumor characterized by high metastatic potential
We found that terminally mature CD56brightCD16+NCR+ Natural Killer (NK) cells infiltrated metastatic Lymph nodes (LN) and activated by cytokines ex vivo, efficiently lysed metastatic lymph node derived melanoma cells [11]
There are several recent studies indicating that NK cells infiltrate human solid tumors and that NK cell numbers have a prognostic value for patient evolution and/or response to treatment [14]
Summary
Melanoma is an aggressive skin tumor characterized by high metastatic potential. SLN biopsy procedure is an important prognostic and staging tool in melanoma patients with tumors more than 1 mm in thickness [1]. SLN represents an important immune system headquarter, especially for the T-cell priming and differentiation and maturation of NK cells. The analysis of the immunological parameters (localization of immune cells and interactions with other cell types) and their prognostic impact are crucial to consider, for setting up future designs of adjuvant immunotherapy. Several studies have investigated T cell, dendritic cell and macrophage distribution and reactivity in SLN+ from melanoma, breast cancer and gastric cancer patients [2,3,4,5,6,7]. Rare studies analyzed NK cells, mainly because, until recently, there was no recognized single marker staining to detect effectively these cells in situ
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