Homeostasis of hepatic Natural Killer cells and their role in the physiopathology of liver metastasis of colon cancer

Natural Killer (NK) cells are innate lymphocytes that are critical in the defense against tumors and pathogens. They comprise up to 15% of total circulating lymphocytes but represent approximately 30% of the intra-hepatic lymphocytes. While the phenotype and functions of these cells have been extensively studied in peripheral blood (PB), a full characterization of resident hepatic NK cells (H-NK) is still lacking. Here we describe the phenotypic features of NK cells from specimens of healthy human liver obtained from patients undergoing surgical resections of liver metastasis of colo-rectal adenocarcinoma (CRA). The fact that these tissues specimens are free of any disease has been confirmed both macro- and microscopically. Additionally, the present study also compares the phenotype of tumor-infiltrating NK cells (TI-NK) with H-NK from the same donors. Our results show that the repertoire of activating and inhibitory NK cell receptors of resident H-NK cells is similar to that of both PB-NK and TI-NK cells within the same patients. However, we found a striking dissimilarity between PB-NK and H-NK in the expression of several surface molecules involved in the migration, adhesion and homing of NK cells. In contrast, very few differences were observed in the expression of these “homing” molecules between H-NK and TI-NK. Also in line with what has been observed in PB-NK, the analyses of NK cell subsets in both healthy liver and metastatic lesions of CRA revealed the existence of two subsets of CD56pos/CD16neg and CD56pos/CD16pos expressing distinct receptor repertoires. This notwithstanding, while the ratio of CD56pos/CD16neg to CD56pos/CD16pos NK cells in PB is approximately 1:9, the one observed in healthy liver is 1:1. A similar 1:1 ratio of the two subsets is also maintained within NK cells infiltrating the liver metastasis of colon cancer, although the overall number of NK cells in tumor is significantly lower when compared to the frequency of resident hepatic NK cells. Despite the fact that the phenotype of TI-NK cells generally mirrors the one of H-NK, our data also demonstrate that α5 integrin is significantly and highly up-regulated on TI-NK as compared to H-NK. Therefore, we hypothesize that the adhesion molecule α5 integrin is involved in the retention of H-NK cells in the tumor microenvironment and that this biologic phenomenon might be associated with the reduction of tumor mass or a better prognosis of disease.