UCLA

Recent advancements in our understanding of anti-tumor immune responses and cancer biology have revealed an elaborate interaction between immune effectors as well as transformed cells in the tumor microenvironment. Effectors of the immune system are known to modulate the maturation of tumor cells and to select for cancer with reduced immunogenicity. The same effector mechanisms are likely responsible for shaping the development of healthy stem cells for the ultimate goal of repair and regeneration of damaged tissues and the discontinuation of chronic inflammation.

Natural Killer (NK) cells were first described based on their ability to mediate tumor cell lysis without prior sensitization, however much of their effector functions and dynamic interaction with cells in the microenvironment are still not completely understood. Many studies have demonstrated that NK cells may recognize and become activated by irradiated or stressed cells; yet, currently no studies have investigated the role of NK cells in selection and differentiation of stem cells and potential role of NK cells in the resolution of inflammation. The established paradigm suggests that NK cells are only capable of eliminating defective cells that arise in the body; but, data obtained in this study indicate that the functions of NK cells are not as limited as we once thought.

This study provides evidences that tumor cells and virally infected cells are not the only targets of NK cell-mediated cytotoxicity. Immune cells and healthy stem cells are also susceptible to lysis. NK cells obtained from the peripheral blood or those that have infiltrated into tumors have been shown to be cytotoxicity inactivated or also known as "anergized". In this study, an array of mediators that cause anergy in NK cells have been identified and extensively studied. Initiation of the anergic state in NK cells was once thought as an end-point, a last stop before apoptosis; however, presented data will demonstrate that anergy is a physiological stage that NK cells undergo to help support differentiation of stem cells. Taken together, all of the results provide a novel role for NK cells as effector cells in selection, differentiation and resistance of both transformed and healthy stem cells.