Reduced CD160 Expression Contributes to Impaired NK-cell Function and Poor Clinical Outcomes in Patients with HCC

Abstract

: We previously reported that deficiencies in natural killer (NK)-cell number and function play an important role in the progression of hepatocellular carcinoma (HCC). However, the mechanisms underlying this phenomenon remain obscure. In this study, we analyzed the expression of CD160 on intrahepatic NK cells by evaluating peritumoral and intratumoral tissues of 279 patients with HCC and 20 healthy livers. We observed reduced expression of CD160 on intratumoral NK cells, and patients with lower CD160 cell densities within tumors exhibited worse disease and a higher recurrence rate. High-resolution microarray and gene set enrichment analysis of flow cytometry-sorted primary intrahepatic CD160⁺ and CD160^- NK cells of healthy livers indicated that human CD160⁺ NK cells exhibited functional activation, high IFNγ production, and NK-mediated immunity. In addition, global transcriptomic analysis of sorted peritumoral and intratumoral CD160⁺ NK cells revealed that intratumoral CD160⁺ NK cells are more exhausted than peritumoral CD160⁺ NK cells and produce less IFNγ. High levels of TGFβ1 interfered with production of IFNγ by CD160⁺ NK cells, blocking of which specifically restored IFNγ production in CD160⁺ NK cells to normal levels. These findings indicate that reduced numbers of CD160⁺ NK cells, together with the functional impairment of CD160⁺ NK cells by TGFβ1, contribute to tumor immune escape. In addition, restoring the expression of CD160 and blocking TGFβ1 appear a promising therapeutic strategy against liver cancer. SIGNIFICANCE: These findings show that reduced number and function of CD160⁺ NK cells in the tumor microenvironment contributes to immune escape of HCC; blocking TGFβ1 restores IFNγ production of CD160⁺ NK cells.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/23/6581/F1.large.jpg.