Role of Natural Killer Cells in Uveal Melanoma

SIMPLE SUMMARY: Metastatic Uveal Melanoma (MUM) is a lethal malignancy with no durable treatment available to date. A vast majority of patients with MUM present with liver metastasis. The liver harbors metastatic disease with an apparent lack of a cytotoxic T cell response. It is becoming evident that MUM is not an immunologically silent malignancy and the investigation of non-T cell anti-tumor immunity is warranted. In this review, we highlight the relevance of Natural Killer (NK) cells in the biology and treatment of MUM. Potent anti-NK cell immunosuppression employed by uveal melanoma alludes to its vulnerability to NK cell cytotoxicity. On the contrary, micro-metastasis in the liver survive for several years within close vicinity of a plethora of circulating and liver-resident NK cells. This review provides unique perspectives into the potential role of NK cells in control or progression of uveal melanoma. ABSTRACT: Uveal melanoma has a high mortality rate following metastasis to the liver. Despite advances in systemic immune therapy, treatment of metastatic uveal melanoma (MUM) has failed to achieve long term durable responses. Barriers to success with immune therapy include the immune regulatory nature of uveal melanoma as well as the immune tolerant environment of the liver. To adequately harness the anti-tumor potential of the immune system, non-T cell-based approaches need to be explored. Natural Killer (NK) cells possess potent ability to target tumor cells via innate and adaptive responses. In this review, we discuss evidence that highlights the role of NK cell surveillance and targeting of uveal melanoma. We also discuss the repertoire of intra-hepatic NK cells. The human liver has a vast and diverse lymphoid population and NK cells comprise 50% of the hepatic lymphocytes. Hepatic NK cells share a common niche with uveal melanoma micro-metastasis within the liver sinusoids. It is, therefore, crucial to understand and investigate the role of intra-hepatic NK cells in the control or progression of MUM.