Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches

Abstract

Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as second-line therapy with limited and variable success. Natural killer (NK) cells are an essential component of innate immunity against cancer and changes in phenotype and function have been described in patients with HCC, who also show perturbations of NK activating receptor/ligand axes. Here we discuss the current status of NK cell treatment of HCC on the basis of existing evidence and ongoing clinical trials on adoptive transfer of autologous or allogeneic NK cells ex vivo or after activation with cytokines such as IL-15 and use of antibodies to target cell-expressed molecules to promote antibody-dependent cellular cytotoxicity (ADCC). To this end, bi-, tri-and tetra-specific killer cell engagers are being devised to improve NK cell recognition of tumor cells, circumventing tumor immune escape and efficiently targeting NK cells to tumors. Moreover, the exciting technique of chimeric antigen receptor (CAR)-engineered NK cells offers unique opportunities to create CAR-NK with multiple specificities along the experience gained with CAR-T cells with potentially less adverse effects.

Development of a Predictive Immune-Related Gene Signature Associated With Hepatocellular Carcinoma Patient Prognosis

“…Indeed, preclinical studies have found that NK cells and T cells are able to kill HCC tumor cells in vitro, and there are many factors in HCC microenvironments contribute to reduced intratumoral NK cell function. [41][42][43] We found that high-risk HCC patients exhibited significantly reduced NK cell infiltration relative to low-risk patients (P ¼ 0.002). This reduced NK cell infiltration likely contributes to the immune evasion and progression of this cancer type, potentially explaining the differences in survival outcomes between these 2 risk groups.…”

Immunotherapy for targeting cancer stem cells in hepatocellular carcinoma

“…Although some progress is also being made to apply NK cell-based therapies against solid tumors, response rates in patients remain to be unsatisfied 163 . In HCC, several NK-cell based I/II phase clinical trials are in progress, such as, autologous/allogeneic NK cells infusion or in combination with other therapies (NCT03319459, NCT04162158, NCT03592706), anti-MUC1 CAR-NK cells (NCT02839954), and so on 168 . Moreover, related studies have showed that chemotherapy or radiation therapy can increase the amounts of CSCs in various tumor and induce up-regulating NKG2D ligands MICA and MICB on CSCs, indicating that NK cell-based immunotherapies in combination with radiation therapy or chemotherapy could better eradicate CSCs in HCC 169 .…”

PKM2-Induced the Phosphorylation of Histone H3 Contributes to EGF-Mediated PD-L1 Transcription in HCC

“…Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with a high mortality rate (Du et al, 2016;Nie et al, 2018). Immune escape is emerging as important contributors to the pathogenesis of HCC through remodeling the tumor microenvironment (Liu et al, 2018a;Mantovani et al, 2020). Aberrant overexpression of programmed death-ligand-1 (PD-L1) has been observed in hepatocellular carcinoma cells (Zhong et al, 2017).…”