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Natural Killer (NK) cells acquire memory-like properties following a brief stimulation with IL-12, IL-15 and IL-18. These IL-12/15/18-preactivated NK cells, also known as cytokine-induced memory-like (CIML) NK cells, have been revealed as a powerful tool in cancer immunotherapy due to their persistence in the host and their increased effector functions. Several studies have shown that NK cells modulate their metabolism in response to cytokine-stimulation and other stimuli, suggesting that there is a link between metabolism and cellular functions. In this paper, we have analyzed metabolic changes associated to IL-12/15/18-stimulation and the relevance of glycolytic pathway for NK cell effector functions. We have found CIML NK cells are able to retain a metabolic profile shifted towards glycolysis seven days after cytokine withdrawal. Furthermore, we found that treatment with 2-DG differently affects distinct NK cell effector functions and is stimuli-dependent. These findings may have implications in the design of NK cell-based cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Background: The interplay between the immune system and cancer cells has come to the forefront of cancer therapeutics, with novel immune blockade inhibitors being approved for the treatment of an increasing list of cancers. However, the majority of cancer patients still display or develop resistance to these promising drugs. It is possible that cancer stem cells (CSCs) are contributing to this therapeutic resistance. Although CSCs usually represent a small percentage of the total number of cancer cells, they are endowed with the ability of self-renewal and to produce differentiated progeny. Additionally, they have shown the capacity to establish tumors after transplantation to animals, even in small numbers. CSCs have also been found to be resistant to various anti-cancer therapies, including chemotherapy, radiation therapy and, more recently, immunotherapy. This is true despite the sensitivity of CSCs to lysis in vitro by natural killer (NK) cells, the main effector cells of the innate immune system. In this paper the expression of ligands specific for NK cells on CSCs, the intracellular network responsible for the expression of the NK cytotoxicity receptors, and the status of activation of NK cells in the tumor micro-environment are reviewed. The aim of this review is to highlight potential strategies for overcoming CSC immune resistance, thereby enhancing the efficacy of current and future anti-cancer therapies.Therapeutic implications: NK cell activation in the tumor micro-environment through drugs neutralizing inhibitory immune receptors, and combined with other drugs harnessing the potential of the adaptive immune system, could be the most effective approach for attacking both stem cell and non-stem cell cancer populations. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are functionally suppressed in the glioblastoma multiforme (GBM) tumor microenvironment. We have recently shown that survival and differentiation of cancer stem-like cells (CSCs)/poorly differentiated tumors are controlled through two distinct phenotypes of cytotoxic and non-cytotoxic/split anergized NK cells, respectively. In this paper, we studied the function of NK cells against brain CSCs/poorly differentiated GBM and their NK cell-differentiated counterparts. Brain CSCs/poorly differentiated GBM, differentiated by split anergized NK supernatants (supernatants from NK cells treated with IL-2 + anti-CD16mAb) expressed higher levels of CD54, B7H1 and MHC-I and were killed less by the NK cells, whereas their CSCs/poorly differentiated counterparts were highly susceptible to NK cell lysis. Resistance to NK cells and differentiation of brain CSCs/poorly differentiated GBM by split anergized NK cells were mediated by interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Brain CSCs/poorly differentiated GBM expressed low levels of TNFRs and IFN-γRs, and when differentiated and cultured with IL-2-treated NK cells, they induced increased secretion of pro-inflammatory cytokine interleukin (IL)-6 and chemokine IL-8 in the presence of decreased IFN-γ secretion. NK-induced differentiation of brain CSCs/poorly differentiated GBM cells was independent of the function of IL-6 and/or IL-8. The inability of NK cells to lyse GBM tumors and the presence of a sustained release of pro-inflammatory cytokines IL-6 and chemokine IL-8 in the presence of a decreased IFN-γ secretion may lead to the inadequacy of NK cells to differentiate GBM CSCs/poorly differentiated tumors, thus failing to control tumor growth. [ABSTRACT FROM AUTHOR]

Our knowledge of the mechanisms underlying tumor-specific immune response and tumor escape has considerably increased. HLA class I antigen defects remain an important tumor escape mechanism since they influence the interactions between tumor cells and specific T and NK cells in the course of malignant disease. We have studied here HLA class I expression in six subcutaneous metastases obtained from a melanoma patient immunized with an autologous melanoma cell vaccine (M-VAX). We report in this paper that HLA class I antigen expression on these metastatic lesions strongly correlated with the course of the disease. The three metastases that were partially regressing at the time of their excision showed a strong HLA class I expression, whereas the progressing ones showed a very weak or negative staining with most of the anti-HLA class I mAbs used. Real-time quantitative PCR of the samples obtained from microdissected tumor tissue revealed a significant difference in the mRNA levels of HLA-ABC heavy chain and β2m between the two types of metastases, i.e., lower levels in progressing metastases and high levels in regressing ones, confirming the immunohistological findings. This is, to our knowledge, the first report where the clinical outcome of different HLA class I positive and negative melanoma metastases can be clearly correlated with the regression and progression of the disease, respectively. [ABSTRACT FROM AUTHOR]

Information about several papers discussed at the Fifth International Symposium on CD1 and Natural Killer T (NKT) Cells held on March 23-27, 2009 in Kamkura Japan. Topics include the studies on innate immunity, the type 1 NKT cells or invariant NKT (iNKT) cells and the strategies to improve NKT cell immunotherapy for diseases. The symposium featured several NKT cells investigators including Masaru Taniguchi, Edward S. Morse and Louis Agassiz.