Field of Study
Our lab focuses of the natural killer cell, part of the innate immune system. We research these cells in both humans and mice, from molecular biology all the way to clinical application, including drug development.
Natural killer cells are an important part of our immunosurveillance system, so their ability to recognize and kill cancerous cells is of particular interest. Work in our lab has looked into the effect of immunoediting by NK cells, and we recently showed that an NK activating receptor, NKp46, influences FN1 expression by tumors, ultimately affecting metastatic ability (Glasner et al. Immunity 2018). We have also discovered immune-evasion properties of oncogenes, helping to understand the clinical importance of these mutations (Elias et al. Blood 2014). Our understanding of inhibitory receptors on NK cells has even allowed us to generate novel checkpoint inhibitors, including one which is currently in pre-clinical development (NectinTX).
Peter Medewar famously asked how the maternal immune system tolerates the semi-allogeneic fetus. While this question remains unanswered, understanding of NK cells, which make up a majority of the lymphocytes in the human placenta in the first trimester of pregnancy, may help solve this mystery. We showed that NK cells in the placenta are not merely involved in immunity, but also influence the developmental processes of tissues supporting the fetus (Hanna et al. Nature Medicine 2006).
More recently, we also showed that NK cells remember pregnancy (Gamliel et al. Immunity 2018). Following a woman’s first pregnancy, a subset of trained NK cells waits in the uterus for the next pregnancy. If this pregnancy arrives, the NK cells are ready to secrete a variety of factors and help the placenta develop. This may help explain some of the increased risks in first pregnancy which have been linked to poor placental development.
NK cells are also the cornerstone of the body’s response to infection by a variety of viruses. People with mutations impairing NK function are at increased susceptibility to viral infection, especially with herpesviruses. We study a number of viruses in our lab, including influenza, CMV, HSV-1, HHV-6/7, HMPV, Zika, and reovirus.
Viruses are quite complex, many existing latently for a host’s whole life, so naturally they have developed many mechanisms for evading the human immune system. This has been a field of particular interest in our group (Glasner et al. J Virology 2018, Charpak-Amikam et al. Scientific Reports 2018, Enk et al. Cell Reports 2017, Diab et al. Oncotarget 2016, Schmiedel et al. J Virology 2016, Yamin et al. Cell Reports 2016, Bauman et al. Oncotarget 2016, Schmiedel et al. Elife 2016, Seidel et al. Cell Reports 2015). We were, in fact, the first to show viral targeting of human transcripts using miRNAs (Stern-Ginossar et al. Science 2007).
We also study direct interaction between NK receptors and viruses (Mandelboim et al. Nature 2001, Bar-On et al, J Virology 2017, Duev-Cohen et al. Oncotarget 2016, Diab et al. Oncotarget 2016). As we have seen in cancer immunotherapy, understanding the immune response at this level can have great therapeutic potential.
Our interests also include a closer look at the molecular biology regulating immune function, particularly at the RNA level. We have found several RNA binding proteins which regulate various immune molecules (Berhani et al. J Immunology 2017, Reches et al. J immunology 2017, Nachmani et al. Nature Communications 2014). mRNA stability and miRNAs are also an important part of immune regulation related to NK cells (Toledano et al. J Immunlogy 2018, Tsukerman et al. Oncotarget 2014, Tsukerman et al. Cancer Research 2012, Nachmani et al. Nature Immunology 2010).
Bacteria and Fungi
Recent work has shown that NK cells are important in the immune response to bacteria and fungi. We found that certain bacteria can directly bind NK receptors, altering NK function (Gur et al. Immunity 2015). We also found that common fungal pathogens such as Candida glabrata are directly recognized by NK cells (Vitenshtein et al. Cell Host and Microbe 2016). Our work on Fusobacterium nucleatum may help explain the worse prognosis observed in patients with colorectal cancer colonized by F. nucleatum, and guide future treatment of these patients.
Other works in our lab showed that NK cells are involved in urinary tract infections, one of the most common bacterial infections in humans (Isaacson et al. Cell Reports 2017, Gur et al. Cell Host and Microbe 2013). This understanding has helped us develop new immune-stimulatory treatments for cancer.