Abstract
Previous studies support the role of natural killer (NK) cells in controlling hepatocellular carcinoma (HCC) progression. However, ambiguity remains about the multiplicity and the role of different NK cell subsets, as a pro-oncogenic function has been suggested. We performed phenotypic and functional characterization of NK cells infiltrating HCC, with the corresponding nontumorous tissue and liver from patients undergoing liver resection for colorectal liver metastasis used as controls. We identified a reduced number of NK cells in tumors with higher frequency of CD56BRIGHTCD16− NK cells associated with higher expression of NKG2A, NKp44, and NKp30 and downregulation of NKG2D. Liver-resident (CXCR6+) NK cells were reduced in the tumors where T-bethiEomeslo expression was predominant. HCCs showed higher expression of CD49a with particular enrichment in CD49a+Eomes+ NK cells, a subset typically represented in the decidua and playing a proangiogenic function. Functional analysis showed reduced TNF-α production along with impaired cytotoxic capacity that was inversely related to CXCR6−, T-bethiEomeslo, and CD49a+Eomes+ NK cells. In conclusion, we identified a subset of NK cells infiltrating HCC, including non-liver-resident cells that coexpressed CD49a and Eomes and showed reduced cytotoxic potential. This NK cell subset likely plays a regulatory role in proangiogenic function.
Highlights
Natural killer (NK) lymphocytes are innate immune cells that are known for their capacity to kill transformed or virus-infected cells [1,2,3].Besides their cytotoxic function, NK cells release cytokines such as TNF-α and IFN-γ that can control virus infection
The characteristics of the intrahepatic NK cells compartment were studied in paired liver and hepatocellular carcinoma (HCC) samples obtained at surgical resection and in normal liver tissue surrounding colorectal metastases as a control
Data from the literature support the relevance of NK cells in controlling neoplastic progression, in HCCs [26,38]
Summary
Natural killer (NK) lymphocytes are innate immune cells that are known for their capacity to kill transformed or virus-infected cells [1,2,3]. Besides their cytotoxic function, NK cells release cytokines such as TNF-α and IFN-γ that can control virus infection. In addition NK cells are involved in the maturation of dendritic cells [4,5] and display regulatory functions on the immune response by killing antigen-specific T cells [6] and stellate cells to limit liver fibrosis. The secretion of angiogenic factors to promote placental growth has been reported by specific organ-resident NK cells known as decidual NK cells (dNK) [7].
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