Cytokine modulation of natural killer cells to develop a novel immunotherapy

Abstract

Over many decades, numerous studies have had the common aim of improving cancer treatments, with several promising approaches proposed. Hepatocellular carcinoma (HCC) is one of the most common type of primary liver cancer, with very high death rates and increasing recurrence. However, current treatments are not successful, therefore great effort has been put into improving HCC therapies with a focus on immunotherapy. Recently, NK cells have been the centre of attention of translational medicine due to their innate cytotoxic potential and anti-tumour functions. The many challenges encountered in the in vitro manipulation of NK cells, though, have significantly hindered the development of NK-based therapies. This study aims to improve NK cell culture protocols, focussing on the expansion of NK cells in a feeder-free culture using soluble cytokines, to develop an improved therapy line for HCC. Here we focus on IL-21, to unveil its role in NK cell expansion and function. The results demonstrate that a short exposure to IL-21 causes a rapid and increased NK cell expansion. NK cells present a phenotype of mature and immature cells, expressing CD117, NKG2A, CD16, but lack CD57. Cells upregulate STAT3 and show high metabolic rates. Pre-activation of IL-21+IL-15, followed by IL-18+IL-2 combination causes the highest antitumour function of NK cells against HCC cell lines. However, the IL-21 effect was masked in chimeric antigen receptor (CAR)-engineered NK cells, though cytokine-primed CAR-NK showed a significant advantage in killing HCC cell lines. These findings suggest important features of NK cells, which can be exploited for the improvement of NK culturing protocols and of HCC therapies.

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Identifiers

ORCID for Salim Khakoo: orcid.org/0000-0002-4057-9091

ORCID for Aymen Al-Shamkhani: orcid.org/0000-0003-0727-4189

ORCID for Matthew Blunt: orcid.org/0000-0003-1099-3985

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