NKT Cell Exacerbation of Liver Metastases Arising from Melanomas Transplanted into Either the Eyes or Spleens of Mice

Uveal melanoma is the most common intraocular tumor in adults. Liver metastasis is the leading cause of death in uveal melanoma patients and it has been reported that approximately 95% of patients who die of uveal melanoma have liver metastases.1 At the present time, there are no therapeutic modalities that significantly control liver metastases or extend the 5-year survival of patients harboring liver metastases arising from uveal melanomas.2 Although immunotherapy has been touted as a promising therapeutic modality, the results to date have been disappointing.3,4 A possible explanation is the observation that tumors employ a wide array of strategies for evading immune surveillance. These mechanisms include downregulation of antitumor immune responses by CD4+CD25+ regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), M2 macrophages, and natural killer T (NKT) cells.3,5,6 In recent years, it has become clear that innate T cells, such as NKT cells, play an important role in modulating the adaptive immune response.7 NKT cells express both T-cell and NK-cell receptors, but unlike conventional T cells that respond to peptides presented by conventional major histocompatibility (MHC) molecules, NKT cells recognize lipid antigens presented by CD1d, a nonclassic MHC molecule. Despite being a small proportion of the total T lymphocyte population (1%–3% of circulating T cells in mice and 0.02%–0.2% in humans),8,9 NKT cells are involved in a broad range of immunologic phenomena, including autoimmune diseases, such as type 1 diabetes, graft-versus-host disease, graft rejection, airway hypersensitivity, and cancer.7,10,11 CD1d-restricted NKT cells can function as either effector or regulatory cells. In cancer, type I NKT cells exert antitumor effects by producing IFN-γ, which activates NK cells and CD8+ T cells and by activating dendritic cells. By contrast, type II NKT cells, which recognize a more diverse array of glycolipids presented by CD1d, inhibit tumor immunity by inducing regulatory cytokines, such as TGF-β, or by recruitment of Tregs.11,12 NKT cells also function differently, depending on their anatomic location. Murine liver–derived NKT cells are protective and control tumor growth, unlike thymic and splenic NKT cells, which have far less antitumor effects but have immunoregulatory properties.13 The liver is the target organ for metastases arising from uveal melanoma. It also has the highest NKT-cell/T-cell ratio in the body. Up to 50% of the lymphocytes in the liver are NKT cells.14–16 Given the wide range of activities mediated by NKT cells, we sought to determine the role that liver NKT cells have in the development of liver metastases arising from intraocular melanomas.