Immune regulation: Uncovering the ‘brakes’ on immune activation

T cells drive immune activation and promote clearance of infections and cancer. However, their function can also 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. Immunoregulatory mechanisms also suppress beneficial anti-tumour T cell responses to drive deleterious immunosuppression in cancer. Immunoregulatory mechanisms therefore function as ‘brakes’ on immune activation and have important consequences in inflammation and cancer.

Fundamental discovery in the field of immunoregulation will pave the way for immune-based therapies for patients with presently incurable diseases.

Immunoregulatory mechanisms and cancer immunosuppression

Clinical responses of advanced metastatic melanoma patients to immune checkpoint inhibitor therapy.

Figure 1. Clinical responses of advanced metastatic melanoma patients to immune checkpoint inhibitor therapy. Progression-free survival (RECIST criteria) of patients with advanced melanoma at a median follow-up of 2 years in all patients assigned to treatment. Responses of individuals randomised to either anti-CTLA-4 (ipilimumab), or combined anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab) treatment groups are shown. Data from Hodi et al., Lancet Oncol 2016)

Immunotherapies targeting the immunoregulatory immune ‘checkpoints’ PD-1 and CTLA-4 have revolutionised the treatment of patients with certain types of metastatic cancer, for example in those with advanced metastatic melanoma (Fig. 1) and PD-L1+ non-small cell lung cancer.

However, these therapies, which are thought to work primarily by affecting CD8+ T cells, are ineffective at inducing durable responses in a majority of patients and a majority of cancer types. There is a need to develop new and mechanistically distinct modes of cancer immunotherapy. A major aim of the fundamental immunology research in the laboratory is to uncover new immunoregulatory mechanisms whose dysregulation in tumours contributes to cancer immunosuppression. A second major aim of the research is to uncover immunoregulatory mechanisms that function to restrict autoimmune and allergic inflammation. The research aims to inform the development of new immune based therapies in the mid-term for patients with autoimmune and allergic inflammation and cancer.

Research themes

Mechanisms of regulatory T (Treg) cell development and maintenance in inflammation and cancer

Cells with dedicated immunoregulatory function exist within the T cell lineage. Whereas effector CD4+ and CD8+ T cells promote immune activation, CD4+ regulatory T (Treg) cells, dependent upon the transcription factor Foxp3, suppress their function, preventing excessive autoimmune and allergic reactions (Fig. 2). Treg cells therefore represent an important immunoregulatory mechanism underpinning peripheral tolerance and stability of Treg populations is required throughout life to prevent lethal inflammation. In cancer, however, regulatory T cells powerfully limit effector responses and their stability is a barrier to immune-mediated clearance of disease. This project aims to better define the transcriptional and epigenetic mechanisms that drive Treg lineage specification. We are also interested in the signalling, transcriptional and epigenetic mechanisms that control Treg population dynamics and lineage stability during inflammation and cancer, and the potential for immunotherapies to affect these aspects of Treg biology.

Immunoregulatory function within the T cell lineage.

Figure 2. Immunoregulatory function within the T cell lineage. CD4+ effector and regulatory T (Treg) cells arise from common precursor cells within the thymus and periphery by exert opposing functions. Treg-mediated restraint of effector cell function is a critical immunoregulatory mechanism required to prevent lethal inflammation. Peripheral tolerance is also maintained by extrinsic immunoregulatory signals received by conventional T cells in tissues.

We have shown that alternate lineage repression by the transcriptional repressor BACH2 is required to stabilise early Treg cell development with consequences for immune homeostasis (Nature 2013, Nature 2015) and tumour immunity (J Clin Invest 2016). We have shown that the PHD family of HIF TF prolyl hydroxylases enable induced Treg differentiation to be modulated by extracellular oxygen concentrations and drive permissivity of the lung to tumour metastasis (Cell 2016). These findings show that the immunoregulatory mechanisms involved in Treg differentiation have consequences for both inflammation and anti-cancer immunity.

Molecular and cellular mechanisms of tumour immunosuppression

Cancers adapt to their immune environment to evade attack. According to the cancer immunoediting hypothesis (Fig. 3), 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. 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.

How is the function of the immune system suppressed during tumour development?

Figure 3. Phases of tumour development 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 a variety of components of the innate and adaptive immune systems, including CD8+ T cells and NK cells. This process results, referred to as immunoediting, results in an ‘equilibrium’ phase, during which pressure from the immune system contributes to selection of tumour variants that do not express antigens targeted by the adaptive immune system or have developed mechanisms to suppress immune function. This gives rise to the ‘escape’ phase characterized by recruitment and support of the differentiation and proliferation of immunosuppressive cell types including Treg cells, tumour-associated macrophages and myeloid-derived suppressor cells, expression of inhibitory ligands and such as PD-L1 and production of immunosuppressive factors such as TGF-b resulting in 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. For example, we have found that high levels of extracellular potassium in the tumour microenvironment is profoundly suppressive to T cell activation (Nature 2016). We are examining the adaptations tumours make to evade host immunity using directed tumour evolution and high-throughput sequencing based approaches to uncover new mechanisms of tumour immunosuppression. We are also utilising high-throughput functional genetics to identify novel immunoregulatory mechanisms operating within the tumour microenvironment.

Uncovering the earliest events in innate and adaptive immunity to cancer metastasis

Metastasis of cancer cells from primary tumours to distant organs is a principal cause of cancer morbidity and mortality. Metastases develop in individuals despite the vulnerability of metastasising cancer cells to immune attack. Innate lymphocytes such as natural killer (NK) cells play a critical role in elimination of early metastatic tumour cells. In addition, newly established metastases express similar mutated neo-antigens to the originating tumour but the timing with which neo-antigen-specific CD4+ and CD8+ T cell responses are recruited to early metastases compared with primary tumours, and their phenotype and function, are distinct. Using mouse primary and metastatic tumour models in conjunction with cellular and molecular immunology approaches, this project focusses on gaining a detailed understanding of the earliest immune events that occur upon cancer metastasis and the immunoregulatory mechanisms by their rejection of metastases is prevented.

Research Highlights

(For a full list of publications see below)

A distal enhancer at risk locus 11q13.5 promotes suppression of colitis by Treg cells

CRISPR-based mutagenesis of disease-associated distal enhancer homologs in mice reveals a regulatory switch for signal-driven GARP expression by Treg cells. The function of the enhancer is required for Treg cells to control gut inflammation.

Nasrallah R, Imianowski C, et al.

[PDF] Nature (2020)

BACH2 promotes the functional quiescence and maintenance of resting Treg cells

The transcription factor BACH2 is repurposed following Treg lineage specification and its high expression in resting Treg cells is required for their quiescence and durable maintenance. Durable maintenance of resting Treg cell responses is required for immune homeostasis and cancer immunosuppression.

Grant FM, Yang J, et al.

[PDF] J Exp Med (2020) in press.

Protocols for integrative genome-wide analysis of transcription factor binding and chromatin accessibility in lymphocytes

Experimental and computational protocols to enable integrative analysis of TF binding and chromatin accessibility in lymphocytes.

Sadiyah MF, Roychoudhuri R.

[PDF] Curr Protoc Immunol (2019) 126:e84.

A human monogenic inflammatory disease caused by loss-of-function mutations in BACH2

The discovery of a human monogenic disease resulting from inactivating mutations of BACH2, termed BACH2-related Immunodeficiency and Autoimmunity (BRIDA). The work, resulted from an international collaboration with clinicians and scientists in the UK and the US.

[PDF] Nat Immunol (2017) 18:813-823.

BACH transcription factors in innate and adaptive immunity

A review on BACH family transcriptional repressors in innate and adaptive immunity. We highlight similarities at a molecular level in the cell-type-specific activities of the BACH factors, proposing that competitive interactions of BACH proteins with transcriptional activators of the bZIP family form a common mechanistic theme underlying their diverse actions.

Igarashi K, Kurosaki T and Roychoudhuri R

[PDF] Nat Rev Immunol (2017) 17:437-450.

High levels of extracellular potassium in tumours suppress T cell activation

Cell death within tumours releases intracellular potassium into the extracellular space causing profound suppression of T cell activation and anti-tumour immunity. Engineering CD8+ T cells to be resistant to high extracellular potassium levels in tumours improves adoptive immunotherapy.

[PDF] Nature (2016) 537:539-543.

Oxygen-sensing by T cells promotes cancer metastasis to the lung

The HIF prolyl hydroxylases PHD1, PHD2 and PHD3 mediate sensitivity of T cells to environmental local oxygen concentrations within tissues, promoting Treg cell differentiation and permissivity of the lung to cancer metastasis.

[PDF] Cell (2016) 166:1117-1131

BACH2 functions as an AP-1 repressor in lymphocytes to promote CD8+ T cell memory

The transcription factor BACH2 functions as a steric repressor of AP-1 transcription factors in CD8+ T cells, restraining TCR-driven terminal effector differentiation to preserve long-lived memory CD8+ T cell responses

[PDF] Nat Immunol (2016) 17:851-860.

Commentary by Sidwell and Kallies (Nat Immunol 17:744-5.

The transcription factor BACH2 promotes tumour immunosuppression through its function in Treg cell development

BACH2 promotes tumour immunosuppression through its role in Foxp3+ Treg cell differentiation. These results are consistent with the results of a recent large in vivo screen of host immunosuppressive factors published by the Adams lab.

[PDF] J Clin Invest (2016) 126:599-604.

The transcriptional repressor BACH2 is required for Treg cell development and suppression of lethal inflammation

The transcription factor BACH2 plays a critical role in Treg cell development, required for immunological tolerance and suppression of lethal inflammation.
Commentary by Kallies and Vasanthakumar (Immunol Cell Biol. 91:491-2.

[PDF] Nature (2013) 498:506-10.

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Research Team

  • Rahul Roychoudhuri
     Principal Investigator
  • Jie Yang
     Postdoctoral Scientist
  • Paula Kuo
     Postdoctoral Scientist
  • Sarah Whiteside
     Postdoctoral Scientist
  • Charlotte Imianowski
     Doctoral Scientist
  • Firas Sadiyah
     Doctoral Scientist
  • Tarrion Baird
     Doctoral scientist
  • Panagiota Vardaka
     Research Associate
  • Ilinca Patrascan
     Research Intern
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