Molecular regulation of NK cell functional maturation by the transcription factor BACH2

Natural killer (NK) cells are a specialised immune cell type that form a critical first line of defence against cancer and infection. NK cells recognise cancer cells and infections in a different way to CD8+ T cells. This makes them attractive as alternate targets for immunotherapy. Clinical responses to NK cell-targeted immunotherapies have thus far been modest identifying a need to better understand molecular processes that restrict their function.

NK cells exist in a variety of different states, called functional maturation states. These have important implications for their ability to control infections and cancer. We lack an understanding of how NK cell functional maturation is regulated, though identifying such mechanisms may provide new therapeutic targets in NK cell-based immune therapies. In people, genetic variations in a gene that encodes a transcription factor protein called BACH2 are associated with susceptibility to multiple autoimmune and allergic diseases, caused when the immune system undergoes excessive activation. Recent experiments conducted in our laboratories indicate that BACH2 is expressed in NK cells and negatively regulates their functional maturation with consequences for tumour immunity.

The purpose of this work is to establish the function of BACH2 in NK cells, testing the hypothesis that it is a critical negative regulator of NK cell functional maturation and testing its consequences for homeostasis and immune responses to infection and cancer.

Our proposed study is organised into three aims: Firstly, we will find out how BACH2 affects the behaviour of NK cells under normal conditions, and during infection with influenza, where NK cells can contribute to both viral clearance and excessive inflammation. Secondly, we will examine the effect of BACH2 in NK cell responses against cancer, both in NK cells existing within the body, and upon therapeutic transfer into tumour-bearing hosts. Finally, we will examine the molecular processes that underpin the function of BACH2, finding out where BACH2 binds in NK cell genomes and which genes it regulates.

Collectively, this research will enable a better understanding of how the function of the immune system is controlled to under normal conditions and during infections and cancer. This may enable development of new therapies that work by either restraining or enhancing immune responses in individuals with inflammation, infections and cancer.

Natural killer (NK) cells are cytotoxic innate lymphocytes that form a critical first line of defence against cancer and infection. Unlike CD8+ T cells, recognition of cancer cells by NK cells is independent of neo-antigens and potentiated by defects in antigen presentation, making them attractive as mechanistically distinct targets to CD8+ T cells for cancer immunotherapy. Clinical responses to NK cell-targeted immunotherapies have thus far been modest identifying a need to better understand molecular mechanisms that restrict their function.

NK cells exist in a variety of different states, called functional maturation states. These have important implications for their ability to control infections and cancer. We lack an understanding of negative regulators of NK cell functional maturation, though identifying such mechanisms may provide new therapeutic targets for NK cell-based immunotherapies. BACH2 is a transcriptional repressor whose expression is predominantly restricted to lymphocytes. New data indicates that BACH2 is an intrinsic negative regulator of NK cell functional maturation with consequences for homeostasis and anti-tumour immunity. The purpose of this work is to establish the function of BACH2 in NK cells, testing the hypothesis that it is a critical negative regulator of NK cell functional maturation and testing its consequences for homeostasis and immune responses to infection and cancer.

Our proposed study is organised into three aims: 1. We will determine how BACH2 affects NK cells function under normal conditions, and during influenza infection, where NK cells can contribute to both clearance and immunopathology. 2. We will examine the effect of BACH2 in restraining NK cell responses to cancer. 3. We will map the genome-wide epigenetic and transcriptional changes that occur with NK cell functional maturation and examine the component of the NK cell functional maturation programme controlled by BACH2.

In addition to its immediate impact for basic and pre-clinical academic research (see Academic Beneficiaries), this work will be relevant for the following groups:

A) The biomedical industry: The proposed work will establish a critical molecular pathway that negatively regulates NK cell function. Identification of pathways that negatively regulate immune function is of interest to the industrial sector in their attempts to develop new treatments for patients with autoimmunity and allergy, chronic infections and cancer. Where relevant, we will pursue commercial opportunities generated from this research by developing projects with new and existing industrial collaborators, including CRUK Therapeutic Discovery Laboratories and F-Star Biotechnology (see Pathways to Impact for details). We will engage in industrial collaborations with the assistance of Babraham Institute Enterprise (BIE). BIE is the wholly owned trading arm of the Babraham Institute (BI) and manages, develops and commercialises the Institute's intellectual property portfolio, as well as facilitating collaborations between the Institute and industry. Successful commercial exploitation of the results will have impact by directly fostering UK and global economic growth.

B) The Babraham Institute and affiliates: Should the research lead directly to commercially exploitable outcomes, BIE has arrangements for protection and development of intellectual property and a track record in exploitation of the Institute's science. We will actively pursue commercial opportunities using an approach outlined in the Pathways to Impact section. Commercialisation of Babraham Institute science will directly benefit the Institute and affiliated parties by generating new revenue.

C) The UK skilled workforce: This will have immediate impact by enhancing skills within the UK workforce. Undertaking the proposed research will result in recruitment and training of a post-doctoral researcher at a world-class UK research institute in the fields of tumour immunology, NK cell biology and gene regulation and will enable the postdoctoral researcher to advance their career, potentially towards scientific independence. We encourage researchers to gain skills in bioinformatics and statistics through attendance of regularly held training sessions at the Babraham Institute. These research skills are relevant for both a career in academic or industrial science. The postdoctoral researcher will also gain presentation skills and the opportunity to expand their network of scientific and industrial contacts through the opportunity to attend an International conference, for which funding has been requested.
By being involved in this research, a variety of technical and scientific staff at the Babraham Institute, including Animal Facility technicians and managers, will gain new skills required to perform mouse tumour immunology and NK cell biology experiments. These technical skills will be relevant to a variety of academic and industrial research sectors.

D) Patients and the National Health Service: Immunotherapy is revolutionising the treatment of metastatic cancer. We will publish and present results of this work, thereby informing basic and translational research in NK cell-based cancer immunotherapy with the potential to generate mid- to long-term benefits to healthcare. Development of new treatments will benefit patients and the National Health Service. Such benefits would be realised in the mid- to long-term (5-20 years).

E) The general public: There is significant public interest in the interaction of cancer with the immune system and in development of new immunotherapies. We will engage public audiences with the results of our research through media communications and through presentations and open days (see Communications plan). Both the PIs and the PDRA will take part in Babraham's Annual Schools Days each year of the project.