Accumulation of Tumor-Infiltrating CD49a+ NK Cells Correlates with Poor Prognosis for Human Hepatocellular Carcinoma

Abstract The discovery of CD49a+ liver-resident natural killer (NK) cells in mice alters our view of NK cells and provides another opportunity to study NK cells. Although evidence has suggested roles for NK cells in liver diseases, whether and how CD49a+ NK cells contribute to liver diseases remain unclear. In this study, we observed that accumulation of CD49a+ tissue-resident NK cells in human hepatocellular carcinoma (HCC) was higher than in peritumoral tissues. We studied the exhausted and regulatory phenotypes of CD49a+ tissue-resident NK cells by analysis of protein and mRNA. The proportion of CD49a+ NK cells was positively correlated to the proportion of NK cells expressing inhibitory receptors. In addition, CD49a+ NK cells expressed more of checkpoint molecules PD-1, CD96, and TIGIT. Transcriptomic analysis implicated CD49a+ tissue-resident NK cells in the negative regulation of immune responses. Comparison of murine and human CD49a+ NK cells revealed their distinct characteristics and functions. Finally, accumulation of tissue-resident CD49a+ NK cells in liver tumor was correlated to deteriorating disease condition and poor prognosis. Our findings show that CD49a+ NK cells accumulate in liver tumor and suggest a role for CD49a+ NK cells in the negative regulation of immune responses and the development of HCC.