Intratumor Regulatory Noncytotoxic NK Cells in Patients with Hepatocellular Carcinoma

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.

Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches

“…The dual capability of anti-CD6 monoclonal antibody to enhance killing of cancer cells through its effects on both CD8 + T cells and NK cells opens a new avenue for cancer immunotherapy [92]. Tumor infiltrating NK cells co-expressing CD49a and Eomes of 18 with reduced cytotoxic potential, have been reported in HCC and this NK cell subset was implicated to have proangiogenic function [93].…”

Natural Killer Cells and Type 1 Innate Lymphoid Cells in Hepatocellular Carcinoma: Current Knowledge and Future Perspectives

“…The expression of granzyme, perforin and IFN-γ were all reduced, resulting in a reduced ability to lyse target cells in vitro [136]. The analyses of normal and tumor hepatic tissues have revealed a strong decrease of intratumoral NK cells in tumors compared to non-tumoral tissues [133,134,138]. Regarding the distribution of the different NK cell subsets within tumors, Zecca et al [138] have reported an enrichment in CD56 bright NK cells, associated with decreased expression of CXCR6 and Eomes and an increased frequency of T-bet + and CD49a + CD56 bright NK cells.…”

“…The analyses of normal and tumor hepatic tissues have revealed a strong decrease of intratumoral NK cells in tumors compared to non-tumoral tissues [133,134,138]. Regarding the distribution of the different NK cell subsets within tumors, Zecca et al [138] have reported an enrichment in CD56 bright NK cells, associated with decreased expression of CXCR6 and Eomes and an increased frequency of T-bet + and CD49a + CD56 bright NK cells. In contrast, Sun et al [139] observed a decreased frequency of CD56 bright cells with a corresponding increase of CD56 dim NK cells compared to peri-tumoral tissues.…”

“…In contrast, Sun et al [139] observed a decreased frequency of CD56 bright cells with a corresponding increase of CD56 dim NK cells compared to peri-tumoral tissues. Similar to blood NK cells, the function of intratumoral NK cells is impaired due to the reduced expression of cytotoxic molecules and pro-inflammatory cytokines [134,136,138], indicating that several immunosuppressive mechanisms exerted by the tumor microenvironment are in place to prevent NK cell anti-tumor function. Treatment with recombinant IL-2 or IFN-γ increased NK cell function and activity; however, the cytotoxic activity of NK cells isolated from HCC patients against target cells remains lower compared to patients suffering from other liver-related diseases [132].…”

“…Recent investigations have demonstrated that, in HCC, NK cells upregulated the inhibitory receptors NKG2A, TIM3 and CD96 and downregulated TIGIT, NKG2D, NKp30, NKp46, sialic acid binding Ig-like lectin 7 (Siglec-7) and CD160 expression, which was associated with the impairment of NK cell function and poor prognosis [106,138,139,184,185]. However, some discrepancies may exist between studies as Zecca et al [138] reported increased expression of NKp30 on intratumoral NK cells compared with hepatic NK cells from non-tumoral tissue. An increase in CD96 expression on NK cells was inversely correlated with IFN-γ production.…”