By Yong Yu
Killer T-cell attacking tumour cell. Credit: Alex Ritter, Wellcome Images
Over the past 50 years, fundamental scientific advancements in the field of immunology have unveiled a new strategy to treat cancer: immunotherapy. An alternative to surgery, radiation therapy and chemotherapy, immunotherapy was born from basic research into the understanding of T cells, a specific type of white blood cell that plays a central role in cellular immunity.
Today, ipilumumab and remelimumab are two FDA approved antibodies used to treat metastatic melanoma and mesothelioma, whilst a further 8 antibodies are in clinical trials. These spectacular achievements in the immune management of various tumours build upon an in-depth understanding of T cell differentiation, function, homeostasis and immune response, an understanding which was creatively exploited by translational researchers.
Our team are interested in innate lymphoid cells, or ILCs, a newly discovered arm of the innate immune system that mirrors the function of T cells in the adaptive immune system. In particular, we are interested in group 2 ILCs (ILC2), which have a major role in the early immune response, and are also involved in immune pathologies such as asthma.
What really excites us is that ILC2s and T cells can directly regulate each other by the presentation of peptide antigens or the secretion of cytokines. Looking back at how much we have learnt from the use of T cells in immunotherapy, the next logical step for us is to identify the molecules that will allow us to manipulate ILC2s immune response in order to fight cancer and other diseases.
One way we can try to manipulate the ILCs biology as a potential cancer therapy is by modulating the transcription factors these cells produce. The transcription factors we are looking at are come from the B-cell leukaemia 11 family (Bcl11), in particular Bcl11a and Bcl11b. Our previous research has shown that, in adaptive immune cells, these factors are specifically expressed in B and T cells to regulate their development and function.
We have found that deletion of Bcl11b can induce the reprogramming of T cells into cytotoxic natural killer cells known as induced T-to-natural killer cells (ITNKs). Natural killer cells are rare in the body because of their highly damaging nature, but they have the ability to kill tumour cells both in vivo and in vitro, and this capacity means that they can be exploited in cancer therapies if enough of them are present. T cells on the other hand are far less destructive, and can be found abundantly in the body, circulating in the blood at all times. Hence, by deletion of Bc1llb and development of ITNKs, we have found an alternative way to make the quantities of natural killer cells which would be required to target a tumour in immunotherapy.
To further investigate the role of Bcl11b in cell differentiation, we used a reporter system to track the expression pattern of Bcl11b in the ILCs. Interestingly, we found that Bcl11b is predominantly expressed in ILC2 progenitors that can be traced to the bone marrow. We also found that deletion of Bcl11b led to a complete absence of ILC2s in the body, which points to Blc11b as a crucial transcription factor in ILC2 differentiation. This notion was strengthened by findings that Bcl11b-deficient bone marrow progenitors lost the potential to develop into ILC2 both in vivo and in vitro.
All our data suggests that the right expression levels of Bcl11b during ILC2 development is absolutely critical to getting the right numbers of ILC2 with the right function. Because of this, we think Bcl11b makes an intriguing candidate for modulating ILC2 as part of a potential new cancer therapy. In the near future, we hope that our research will lead to a better understanding of the regulatory pathways of Bcl11b, and their effects on ILC2s. Ultimately, we hope to find new candidate genes like Bcl11b that will enable us to modulate these newly discovered cells in a way that can be used to treat cancer.
Yong Yu is a Postdoctoral Research Fellow in the Mouse Cancer Genetics group at the Wellcome Trust Sanger Institute, working on hematopoiesis and cancer.
- Yong Yu et al. (2015) The transcription factor Bcl11b is specifically expressed in group 2 innate lymphoid cells and is essential for their development. The Journal of Experimental Medicine. DOI: 10.1084/jem.20142318
- Yong Yu et al. (2012) Bcl11a is essential for lymphoid development and negatively regulates p53. The Journal of Experimental Medicine. DOI: 10.1084/jem.20121846