Pharmacological targeting of natural killer cells for cancer immunotherapy.

Natural killer (NK) cells are innate lymphocytes that rapidly respond to cancer cells without prior sensitization or restriction to the cognate antigen in comparison with tumor antigen-specific T cells. Recent advances in understanding NK-cell biology have elucidated the molecular mechanisms underlying the differentiation and maturation of NK cells, in addition to the control of their effector functions by investigating the receptors and ligands involved in the recognition of cancer cells by NK cells. Such clarification of NK-cell recognition of cancer cells also revealed the mechanism by which cancer cells potentially evade NK-cell-dependent immune surveillance. Furthermore, the recent clinical results of T-cell-targeted cancer immunotherapy have increased the expectations for new immunotherapies by targeting NK cells. However, the potential use of NK cells in cancer immunotherapy is not fully understood. In this review, we discuss the current evidence and future potential of pharmacological targeting of NK cells in cancer immunotherapy.

Antimetastatic effects of thalidomide by inducing the functional maturation of peripheral natural killer cells.

Thalidomide and its analogues are known as immunomodulatory drugs (IMiDs) that possess direct antimyeloma effects, in addition to other secondary effects, including antiangiogenic, antiinflammatory, and immunomodulatory effects. Although the involvement of natural killer (NK) cells in the antitumor effects of IMiDs has been reported, it is unclear whether IMiDs inhibit cancer cell metastasis by regulating the antitumor function of NK cells. In this study, we examined the protective effects of thalidomide against cancer metastasis by focusing on its immunomodulatory effects through NK cells. Using experimental lung metastasis models, we found that pharmacological effects of thalidomide on host cells, but not its direct anticancer tumor effects, are responsible for the inhibition of lung metastases. To exert the antimetastatic effects of thalidomide, both γ-interferon (IFN-γ) production and direct cytotoxicity of NK cells were essential, without notable contribution from T cells. In thalidomide-treated mice, there was a significant increase in the terminally differentiated mature CD27lo NK cells in the peripheral tissues and NK cells in thalidomide-treated mice showed significantly higher cytotoxicity and IFN-γ production. The NK cell expression of T-bet was upregulated by thalidomide treatment and the downregulation of glycogen synthase kinase-3ß expression was observed in thalidomide-treated NK cells. Collectively, our study suggests that thalidomide induces the functional maturation of peripheral NK cells through alteration of T-bet expression to inhibit lung metastasis of cancer cells.

Anti-metastatic Effects of Baicalein by Targeting STAT3 Activity in Breast Cancer Cells.

Signal transducer and activator of transcription 3 (STAT3) is considered a potential target for cancer treatment because of its relationship with cellular transformation and tumor initiation and progression. In this study, we aimed to identify a new anti-cancer drug candidate from natural products by targeting STAT3 activity. Using STAT3-luciferase reporter cell line, we screened the chemical library of natural products and found that baicalein, a flavone isolated from the roots of Scutelleria baicalensis, strongly suppressed STAT3 activity in breast cancer cells. Baicalein inhibited STAT3 transcriptional activity and its phosphorylation, and further exhibited anti-proliferative effects in breast cancer cells. Moreover, baicalein suppressed the production of interleukin (IL)-6 and the metastatic potential of breast cancer cells both in vitro and in vivo. Collectively, our study suggests baicalein as an attractive phytochemical compound for reducing metastatic potential of breast cancer cells by regulating STAT3 activity.

Lung-resident natural killer cells control pulmonary tumor growth in mice.

Accumulating evidence indicates the importance of natural killer (NK) cells in controlling tumor growth and metastasis. NK cell subsets display diversities in their function and tissue distribution and Mac-1hi CD27lo NK cells are the predominant population of lung-resident NK cells. Although the lung is a major organ where primary tumor develops and cancer cells metastasize, there is no clear evidence whether circulating NK cells and/or tissue-resident NK cells control tumor growth in the lung. In the present study, we examined an antitumor function of lung-resident NK cells to control pulmonary tumor growth. In an orthotopic lung tumor model, NK cells controlled pulmonary tumor growth, and mature circulating NK cell subsets were increased in tumor-bearing lungs through a C-X-C motif chemokine receptor 3 (CXCR3)-dependent mechanism. Although such increase in migratory NK cell subsets can be blocked by anti-CXCR3 treatment, there was no difference in pulmonary tumor growth in anti-CXCR3-treated mice compared with control mice. In addition to pulmonary tumor growth, lung-resident NK cells, but not migratory NK cells, play a dominant role in controlling metastatic growth of cancer cells in lung. These results strongly indicate an importance of lung-resident NK cells for controlling pulmonary tumor growth.

Establishment of bioluminescent imaging model using murine T cell lymphoma susceptive to NK cell-dependent immune-surveillance.

Although the importance of NK cells as immune effector cells in controlling growth and metastatic dissemination of tumor cells has been widely recognized, it is unclear whether NK cells in different organs similarly control tumor cell growth and metastasis. In the present study, we established a bioluminescent imaging model of mouse T cell lymphoma cells, which are highly susceptive to NK cell-dependent immune-surveillance, to monitor the dissemination of lymphoma cells using an in vivo imaging system. The use of this model is expected to be a highly sensitive method to examine the role of NK cells in controlling lymphoma dissemination in a variety of tissues.