New avenues for melanoma immunotherapy: Natural Killer cells?

Abstract

Human solid malignant tumours may be particularly resistant to conventional therapies. Among solid tumours, immunological features of cutaneous melanoma have been well characterized in the past and today melanoma patients are routinely treated with the anti‐immune checkpoints immunotherapy that has completely changed metastatic melanoma treatment and prognosis. Two cytotoxic cell populations may lead to the physical elimination of tumour cell targets: cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Tumour recognition by CTLs depends on major histocompatibility complex (MHC) class I molecules, while NK cells recognize tumours expressing low or null levels of MHC class I molecules. Despite this well‐established complementarity, NK cells are still left behind in the optimization of innovative immunotherapy approaches. NK cells are members of innate lymphoid cells (ILCs) that play a critical role in early host defence against invading pathogens and transformed cells. Recent findings suggest that NK cell frequencies directly correlate with the overall survival of ipilimumab‐treated melanoma patients. Furthermore, in vitro and in vivo evidences indicate that NK cells can selectively kill cancer stem cells, reducing tumour size and delaying metastatic progression. The aim of this review is to provide a survey of the evidences indicating NK cells as an excellent candidate to complement the newest solid tumour immunotherapy approaches.

Electrotransfer of IL-15/IL-15Rα Complex for the Treatment of Established Melanoma

“…There was also a higher level of NK cells and T-effector cells. Although it is well established that IL-15 or IL-15/IL-15Rα complex can be a potent stimulator of T cytotoxic and NK cells, high levels of IL-15 or the complex can actually result in reduced proliferation, exhaustion, and reduced anti-tumor activity [ 37 ]. A correlation between high IL-15 serum levels, poor prognosis in melanoma patients, and reduced efficacy in treatment with ipilimumab was observed [ 38 ].…”

“…High-dose IL-15 has also been associated with severe adverse effects. including systemic inflammation [ 37 ]. These effects are related to an extended half-life of the IL-15 complex.…”

Critical cancer vulnerabilities identified by unbiased CRISPR/Cas9 screens inform on efficient cancer Immunotherapy

“…Indeed, NK cell based immunotherapies are gaining traction as a treatment approach for a multitude of cancers (reviewed in [97]). Consistent with this, high NK cell infiltration in solid tumors such as melanoma, colorectal, and lung cancer has been shown to correlate with improved prognosis [98–100]. Indeed, inactivation of a number of genes specifically in NK cells, including cytokine‐inducible SH2‐containing protein ( Cish ) increase the cytotoxic capacity of NK cells, particularly in settings of metastatic dissemination [101,102].…”

Tumor Microenvironment: Implications in Melanoma Resistance to Targeted Therapy and Immunotherapy

“…NKs are an important subclass of granular lymphocytes, involved in the recognition and elimination of virus-infected and transformed cells [ 123 , 124 ]. In general, cancer promotes several mechanisms that destabilize the functionality of NKs, determining immune evasion: (1) Hyperproduction of activating ligands that paradoxically block NKs’ receptors and (2) release of immunosuppressive factors, such as TGF-β and prostaglandin E [ 125 ]. Moreover, vemurafenib treatment of melanoma cells induces suppression of NKs activity in vitro, through downregulation of natural killer group 2D (NKG2D) and DNAX accessory molecule-1 (DNAM-1) activating receptors and simultaneous upregulation of MHC-I, which plays an inhibitory effect on NK cells [ 126 ].…”