Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments

Abstract

(controls) were phenotypically characterized. Unsupervised clustering based on the frequency of cells expressing different phenotypic NK-cell markers segregated HCC patients into different cohorts that were compared for outcome. NK-cell cytokine production and cytotoxicity were compared between cohorts with different overall survival (OS) and time to disease recurrence (TTR). By multivariate analysis, age, Child-Pugh class and NK-cell phenotypic clustering could independently identify patients with significantly different OS. NK-cells from patients with better outcome expressed higher levels of cytotoxic granules and CD3z and lower levels of natural cytotoxic receptors (NCRs) that were co-expressed with the inhibitory receptor NKG2A known to negatively regulate NCR function. Cytotoxic function and IFNg production were significantly lower in the cohort of patients with worse outcome compared to controls (p < 0.05). Our results show a role for NK-cells in the control of HCC progression and survival providing the basis for the development of immunotherapeutic strategies to potentiate NK-cell response.

Deficient Natural Killer Cell NKp30‐Mediated Function and Altered NCR3 Splice Variants in Hepatocellular Carcinoma

“…Functional deficiencies of circulating and intralesional NK cells have been demonstrated in various human cancers, including HCC . Nevertheless, the mechanisms responsible for altered NK cell effector function and their association with disease progression remain largely unexplored.…”

Hepatocellular carcinoma: Prospects for natural killer cell immunotherapy

“…However, direct cell to cell NK interactions via the NKp30 receptor with the expanded pool of MDSCs seen in HCC was shown to be associated with inhibition of NK cell activity, further complicating its use as an immunotherapy target. Similarly, the activating receptor NKp46 was found to be upregulated on circulating NK cells from patients with HCC with a poorer prognosis . Taken together, the simple model that increased activating receptor expression of NK cells is beneficial is unlikely to be correct.…”

Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications

“…We recently performed a phenotypic and functional analysis of peripheral blood NK cells from HCC patients. By unsupervised clustering of NK‐cell markers we were able to identify patient cohorts with different overall survival and time to disease recurrence . NK cells from a subset of HCC patients with shorter survival showed impaired cytotoxic function and IFNγ production, together with enhanced multiplicity of cells co‐expressing inhibitory NKG2A and activating NKp30/NKp46 receptors.…”

“…The functional defect of NKG2A/NKp30/NKp46 phenotype had already been described in uterine decidual NK‐cells during early pregnancy, where NKG2A co‐engagement inhibits NKp46‐mediated cytotoxicity and NKp30‐induced IFNγ production. In HCC patients, we showed that treatment with IL15 can lead to partial rescue of NK cell function …”