Project findings could lead to new gene-based cancer treatments
The body’s immune system is a true marvel of biological engineering, made up of structures and processes that cooperate to identify and attack viruses, bacteria and parasites while sparing the body itself. Lymphoid cells (lymphocytes) for example, which wait to respond to microbial invasion, provide resistance against an enormous range of pathogens. However, an unnecessary attack by lymphocytes can have devastating outcomes (such as the development of autoimmune diseases), which is why they need to constantly remain on guard – in a so-called ‘quiescent’ state – and attack only when needed. Thanks to an EU-funded Marie Curie grant, one researcher has been able to make significant advances in understanding the role that certain genes play in maintaining this quiescent state. Signals responsible for maintaining quiescence have been identified, as have certain mechanisms for then translating these signals into action. ‘The aim of this research was really to clarify these crucial questions, and importantly, to better understand how we could exploit our findings to better treat immune-related diseases, leukaemia (cancer of lymphocytes) and improve cancer immune-therapy,’ explains SLFN OF T-CELLS project coordinator Michael Berger from the Hebrew University Medical School in Jerusalem, Israel. ‘I hope this research will convince the scientific community that targeting lymphocyte quiescence has great potential as a new approach to treating leukaemia, and manipulating lymphocytes so to be able to exploit them better to fight pathogens and cancer.’ Building on breakthroughs The findings build on some ground breaking work that was recently done at the Scripps Research Institute as part of Berger’s post-doctoral research. ‘Our discovery of a mouse strain with a mutated Slfn2 gene, elektra, enabled us to provide a dramatic illustration of what happens when quiescence fails,’ explains Berger. ‘The elektra mice showed an abnormally high frequency of lymphocytes in a semi-activated state, and as a result suffered from immunodeficiency.’ Since Slfn2 had no previously known function, Berger and his team at the Hebrew University Medical School were able to demonstrate – for the first time - that the gene plays an essential role in immune defence. ‘We have only started to fully understand that lymphocytes quiescence is critical for the development and function of the immune system and must be actively maintained,’ says Berger. Novel approaches to fighting cancer Indeed, many questions surrounding lymphocytes quiescence still remain, and this is why the SLFN OF T-CELLS project was launched in 2013. During this four-year project, Berger was able to unravel a previously unknown functional connection between the lymphocyte quiescence factor, Slfn2, and protein homeostasis in immune cells. ‘We also demonstrated that targeting Slfn2 leads to impaired survival of leukaemia initiating cells, which suggests that targeting lymphocytes quiescence could serve as a novel approach for treating leukaemia and other types of cancer,’ he says. ‘Finally, we discovered a new mechanism that controls quiescence of certain T-cells by inhibiting their mitochondrial (energy supplier of the cell) proliferation.’ The research has been presented in numerous academic journals and received positive responses from the scientific community. ‘Our goals now are to better understand the role of quiescence in lymphocytes development and function, and to collaborate with pharmacologists in order to develop specific inhibitors and activators of the human homologue of Slfn2 and other quiescence maintaining proteins,’ concludes Berger. The project was completed at the end of 2016.
Keywords
SLFN-OF-T-CELLS, cancer, cells, lymphoid, leukaemia, lymphocytes, immune, slfn2
