Cells whichremained in the shadows for a long time

NK lymphocytes were observed for the first time in the 1970s, but they still have a lot of secrets to reveal. “Scientists were more focused on the actors of adaptive immune response such as T or B lymphocytes which generate a more ‘sophisticated’ immunity. In addition, there are less NK cells in the blood as they represent less than 10% of the white blood cells. Until recently, only few of the markers of these cells were known, which made them more difficult to isolate and study”, explains Nathalie Jacobs.

However, the interest about these cells has been  up and down. Shortly after the discovery of these cells, which are able to spontaneously attack cancer cells, the first studies created strong interest in immunotherapy laboratories. “During the 1980s, researchers tried to amplify the anti-tumor activity of these NK cells, in particular by stimulating them in the presence of a cytokine such as interleukin 2 (IL2). IL2 activated NK cells killed the tumor cells more efficiently and some very encouraging results were obtained with mice”, recalls Nathalie Jacobs.

Unfortunately, the results of clinical trials based on these animal studies were disappointing. Indeed high concentrations of IL-2 needed to be administered in cancer patients in order to allow in vivo activation of NK cells, but in large doses IL-2 is toxic. Moreover IL-2 activates another type of lymphocyte, the regulatory T cells. These lymphocytes ensure regulatory function: they control the immune response in order to prevent an over reaction which would lead to auto-immune diseases. In the present case, these regulatory T cells inhibited the NK cells, the same cells that the researchers were trying to activate.

Succeeding in activating the cells in vivo

“Following this clinical failure, and faced with the lack of understanding  concerning the mechanism of action of these cells, the interest in NK cells faded. Now that we have begun  to understand how these cells work, there has been a new interest in NK cells over the last few years. In order to stimulate them without activating other cells which will inhibit them, other cytokines less toxic than interleukin 2 are being tested in order to use them in immunotherapy”, explains Nathalie Jacobs.  More broadly speaking, the more recent discovery that these cells play an important role in the immune response as a bridge between the innate and adaptive immune responses, has led to researchers once again taking an interest in NK cells today.

Nathalie Jacobs team has focused its research on studying the different functions of NK cells. “We are focusing our work on infections by human papillomaviruses (or HPV), those viruses which can cause cancers and, in particular, uterine cervical cancer. This model therefore offers us the possibility to study the anti-viral response directed against the virus, but also the antitumor response directed against the tumors caused by these viruses.”

A double case-study of  NK cell response, the HPV model

Nathalie Jacobs team is the first one to put forward the hypothesis that NK cells could recognize the human papillomaviruses (HPV) and respond to an infection by these viruses. HPVs which infect the mucosa are very widespread. During their lives, between 50 and 75% of women will be infected by this virus. “Having said that, of all the women infected, less than 1% will develop uterine cervical cancer while more than 90% of them will have eliminated the virus in the two years following infection.”