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

Stefania Mantovani,Mario U Mondelli,Stefania Varchetta,Barbara Oliviero,Dalila Mele

doi:10.3390/cancers12040926

Stefania Mantovani, Mario U Mondelli + Show 3 more

Open Access

https://doi.org/10.3390/cancers12040926

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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.

Highlights

Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancers and develops in a background of chronic viral hepatitis, alcoholic liver disease, or non-alcoholic steatohepatitis (NASH), after a multistep process requiring chronic inflammation leading to necrosis and cirrhosis
The role of NKG2D ligand (NKG2DL) expression is critical for efficient binding to the receptor with consequent Natural killer (NK) cell activation leading to an effective immune response
While most studies focused on rescuing T-cells from exhaustion in an effort to unleash tumor-specific immune responses, it has become clear that NK cells offer several assets to be exploited for immunotherapy, with potentially less adverse effects

Summary

Introduction

Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancers and develops in a background of chronic viral hepatitis, alcoholic liver disease, or non-alcoholic steatohepatitis (NASH), after a multistep process requiring chronic inflammation leading to necrosis and cirrhosis. Receptor-mediated endocytosis via ubiquitination was needed to activate the intracellular signaling pathway which resulted in NK cell activation [32] In this context, the role of NKG2D ligand (NKG2DL) expression is critical for efficient binding to the receptor with consequent NK cell activation leading to an effective immune response. The evidence gathered was further supported by subsequent studies which showed that miRNA-induced by the major HBV envelope polypeptide inhibited the MICA/B expression in HCC cells [42] and that overexpression of the miRNA 25-93-106b cluster determined suppression of MICA in HCC cells [43] Another tumor escape mechanism is NKG2DL shedding caused by several molecules belonging to the a disintegrin and metalloproteinase (ADAM) enzyme family whose activity is regulated by the phosphorylation of their cytoplasmatic tail by intracellular kinases such as polo like kinase 2, MAPK, and protein kinase C [44]. These mechanisms disrupt NK cell activation and anti-tumor response

NK-Based Immunotherapy

NKG2DL-Specific Antibodies for NK Cell-Mediated ADCC

Findings

Conclusions