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The two faces of a Killer

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Immunosuppression and tumor escape from immune recognition are thought to be major factors responsible for the establishment and progression of cancer, however, neither underlying physiological significance nor the exact mechanisms by which immunosuppression occurs are well understood. It is shown that ...

Immunosuppression and tumor escape from immune recognition are thought to be major factors responsible for the establishment and progression of cancer, however, neither underlying physiological significance nor the exact mechanisms by which immunosuppression occurs are well understood. It is shown that freshly isolated tumor infiltrating NK and T cells are not cytotoxic to autologous tumors. Moreover, NK and T cells obtained from the peripheral blood of patients with cancer have significantly reduced cytotoxic activity. It was previously shown that NK sensitive tumors cause loss of NK cell cytotoxicity while increasing IFN-g secretion, a concept which was coined as “split anergy”. On the other hand NK resistant tumors neither induce loss of NK cell cytotoxicity nor IFN-g secretion. Furthermore, following NK cell cultures with sensitive tumor-target cells, the target binding NK cells undergo phenotypic and functional changes expressing CD16-CD56dim/- CD69+ phenotype which may carry out a regulatory function. Significant down-modulation of key cell surface receptors and decrease in intracellular signaling chains and decreased NK and T cell cytotoxic function were also seen in several cancer patients including those of the oral and ovarian cancer patients. Most recently, it was also shown that NK and T cells target and kill cancer stem cells but not their differentiated counterparts. Surprisingly, NK cells were also able to lyse healthy non-transformed hMSCs, hDPSCs and hESCs and hiPSCs significantly more than their differentiated counterparts. In addition, split anergy is also induced in NK cells by MDSCs. These observations indicated a general function for the role of NK and CTLs in shaping the size and the function of stem cells. Based on the accumulated evidence, it was suggested that NK cells may have two significant functions; one that relates to the removal of excess or unwanted proliferating healthy and transformed stem cells and their subsequent selection. The second is to support differentiation and promote tissue regeneration after altering their phenotype to cytokine-secreting cells. This process will not only remove cells that are perhaps damaged and have flaws in the differentiation process or in general are more than needed, but also ensures proper regeneration of tissues and, ultimately result in the resolution of inflammation. Thus, any disturbance in NK cell function or in selection and differentiation of stem cells may result in chronic inflammation, causing continual tissue damage and recruitment of immune effectors to aid in tissue regeneration. Chronic inactivation of NK and T cell cytotoxic functions by the effectors of the tumor microenvironment and induction of split anergy in NK cells may limit their effectiveness in killing stem-like tumors, although they could still limit or slow cancer progression by promoting differentiation of the tumors due to their ability to switch their function to secrete IFN-g. However, the most detrimental consequence for the immune function is to lose both the cytotoxicity and the ability to secrete IFN-g which may represent the end stages of terminal cancer. The proposal is to explore different stages of anergy and inactivation of NK and T cells and relate to eventual progression of cancer due to the scape of cancer stem cells from NK and T cell elimination.


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