T cells drive immune activation and promote clearance of infections and cancer. However, their function can provoke autoimmune and allergic inflammation. The immune system therefore employs a variety of suppressive mechanisms, known as immunoregulatory mechanisms, to restrain excessive T cell activation and prevent autoimmune and allergic inflammation. It is now known that such suppressive mechanisms inhibit anti-tumour immunity to drive deleterious immunosuppression in cancer. Immunoregulatory mechanisms therefore function as ‘brakes’ within the immune system and are important therapeutic targets in infection, inflammation and cancer. This is exemplified by the clinical efficacy of cancer immunotherapies targeting the immune ‘checkpoints’ PD-1 and CTLA-4 in certain cancers.
We believe that fundamental discovery in the fields of immune regulation and cancer immunosuppression will enable development of new and more effective therapies for patients with presently incurable autoimmune and allergic diseases and cancer. Our research falls within three key areas described below.
Regulatory T (Treg) cells are rare immune cells with powerful suppressive functions. Loss of CD4+ Foxp3+ Treg cells results in lethal inflammation, while defects in their function are associated with autoimmunity and allergy. Treg cells also suppress immune responses in cancer. There is intense medical interest in exploiting the powerful biological functions of Treg cells to treat patients with inflammatory diseases, transplantation and cancer. However, most efforts have thusfar been disappointing. We aim to better define mechanisms of Treg development and function, to identify new ways of exploiting or blocking the suppressive function of Treg cells in individuals with inflammation and cancer (Fig. 1).
The immunoregulatory function of Treg cells is a major focus of the laboratory’s research. We have demonstrated the non-redundant requirement for the transcription factor BACH2 in Treg development (Nature 2013). Our findings provided a model of early Treg lineage commitment and explained why genetic polymorphisms at the human BACH2 locus are associated with autoimmune and allergic diseases. We established a now widely-accepted molecular model of how BACH2 functions in lymphocytes (Nat Immunol 2016; reviewed in Igarashi, Kurosaki and Roychoudhuri, Nat Rev Immunol 2017). Our research contributed to the discovery of a new human disease called BACH2-related Immunodeficiency and Autoimmunity (Afzali et al., Nat Immunol 2017). This has led to identification and improved management of patients with BRIDA. We showed that BACH2 promotes Treg-mediated cancer immunosuppression (J Clin Invest 2015). We have subsequently developed cell-based reporter assays for BACH2 function (Scientific Reports 2020), enabling a drug discovery programme in collaboration with Cancer Research UK Therapeutic Discovery Laboratories.
Our group showed that a distal enhancer at the prominent human autoimmune/allergic disease risk locus at chromosome 11q13.5 restricts gut inflammation by promoting expression of the TGF-b docking receptor GARP on Treg cells, revealing a novel mechanism of immune regulation in the gut (Nature 2020). We showed that quiescent cells marked by high levels of BACH2 expression are required for maintenance of Treg responses over time (Grant et al., J Exp Med 2020). We showed that CCR8 expression marks Treg cells with highly suppressive function in tumours but that it is dispensable for their accumulation and suppressive function (Immunology 2021).
Cancers adapt to their immune environment to evade attack. According to the cancer immunoediting hypothesis, tumour development is characterized by an initial ‘elimination’ phase, during which a majority of cancer cells are destroyed by components of innate and adaptive immunity (Fig. 2). This is followed by an ‘equilibrium’ phase, during which pressure from the immune system contributes to evolutionary selection of tumour escape variants that give rise to an ‘escape’ phase characterized by evasion from immune control and unrestrained tumour growth.
While selection of antigen-loss variants represents a mechanism of tumour escape, growth of tumours containing immunogenic epitopes is better explained through an understanding of the critical role of immunosuppression in promoting tumour escape. To achieve this, cancer cells subvert the biochemical, metabolic and ionic environment of tumours to drive immune dysfunction. Using directed tumour evolution and high-throughput CRISPR-based functional genetics, this work aims to identify novel immunoregulatory mechanisms operating within the tumour microenvironment.
We have made progress in understanding mechanisms of tumour immunosuppression. We uncovered mechanisms by which Treg cells contribute to cancer immunosuppression (J Clin Invest 2016). Our group showed that maintenance of durable immunosuppressive Treg responses to cancer require the Treg cells with a quiescent phenotype (J Exp Med 2020). We showed that high interstitial potassium concentrations within tumours limits CD8+ T cell function through suppression of the AKT/mTOR pathway (Nature 2016). We have shown that Treg differentiation is sensitive to local oxygen concentration contributing to lung immune homeostasis but creating a permissive environment for pulmonary cancer metastasis (Cell 2016). We showed that CCR8 marks Treg cells with highly suppressive function within tumours, but is dispensable for their accumulation and function (Immunology 2021). Our research findings and tools form the basis for industrial collaborations with GSK, F-Star Biotechnology and CRUK Therapeutic Discovery Laboratories.
T cell responses are clonally expanded from small numbers of antigen-specific naive precursor cells which arose during thymic development. Upon priming, antigen-specific T cell responses must be maintained over long periods of time to enable T cell memory and durable responses to chronic antigens. Our laboratory is interested in the mechanisms that underpin long-lived T cell responses.
CD8+ T cell memory has been the focus of our prior research. However, we have recently become interested in understanding how clonal Treg responses are maintained over time. To work properly, Treg responses need to be remarkably long-lived: Treg cells produced during a critical time-window in early life need to be maintained throughout life to prevent lethal inflammation. Treg populations are maintained despite reduced thymic output of T cells as we age, and in the definitive absence of thymic output. The transfer of mature Treg cells into Treg-deficient mice establishes a long-lived population that prevents lethal inflammation over the lifespan of the host. Maintenance of Treg responses is also critical to immunoregulatory memory, limiting harmful immune reactions upon re-exposure to allergens and infection, and to the efficacy of Treg cell therapies. Much is known about how Treg cells develop, but we have lacked a framework for understanding how Treg responses are maintained. Our recent work has begun to reshape our thinking about how long-lived Treg responses are organised. We have found that long-term maintenance of Treg populations is dependent upon the presence of a subset of functionally quiescent cells marked by high levels of Bach2 expression (Fig. 3; Grant, Yang et al., J Exp Med 2020). We are developing new tools to understand how long-lived immunoregulatory and immunosuppressive Treg responses are maintained and establishing clinical collaborations to determine the consequences of this for inflammatory and allergic diseases and cancer.
We have a long-standing interest in T cell memory. We conducted one of the earliest multiplexed single-cell gene expression analyses of immune cells revealing unappreciated heterogeneity in memory CD8+ T responses to vaccination (PNAS 2011). We defined transcriptional and epigenetic programmes of vaccine-induced memory T cells (Vaccine 2015, Cell Mol Immunol 2015). We defined molecular mechanisms by which long-lived memory CD8+ T cell responses to viral infection are maintained (Nat Immunol 2016). We showed that long-term maintenance of Treg populations is dependent upon the presence of a subset of functionally quiescent cells marked by high levels of Bach2 expression (J Exp Med 2020). We have contributed to work showing that inhibition of AKT signalling enables expansion of T cells with a long-lived memory phenotype which mediates superior adoptive immunotherapy responses upon transfer into tumour-bearing recipients (Cancer Res, 2015), and that memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy (J Clin Invest, 2015).
(For a full list of publications see below)