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<div id="research_contentid" >
### 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 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’ on immune activation and have important consequences in inflammation and cancer. **Fundamental discovery in the field of immunoregulation will pave the way for new immune-based therapies for patients with presently incurable diseases**.
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 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’ on immune activation and have important consequences in inflammation and cancer. **Fundamental discovery in the field of immunoregulation will pave the way for new immune-based therapies for patients with presently incurable diseases**.

<div style="text-align:center">
<figure style="width:80%; min-width: 350px; display: inline-block; float:none; vertical-align: top; clear: both;">![Clinical responses of advanced metastatic melanoma patients to immune checkpoint inhibitor therapy.]({{ site.url }}{{ site.baseurl }}/images/respic/HodiLancetOncol2016PFS.png)
<figcaption><b>Figure 1. Clinical responses of advanced metastatic melanoma patients to immune checkpoint inhibitor therapy.</b> 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 <i>et al., Lancet Oncol</i> 2016)
</figcaption></figure>
</div>

The clinical efficacy of cancer immunotherapies targeting the immune ‘checkpoints’ PD-1 and CTLA-4 provides powerful examples of the therapeutic significance of immunoregulatory mechainsms. Such therapies have revolutionised the treatment of patients with a variety of advanced cancers, including metastatic melanoma (**Fig. 1**). 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, identifying a need to discover new and mechanistically distinct immunoregulatory mechanisms to drive advances in cancer and inflammatory disease immunotherapy.
The clinical efficacy of cancer immunotherapies targeting the immune ‘checkpoints’ PD-1 and CTLA-4 provides **powerful evidence of the therapeutic relevance of immunoregulatory mechainsms**. Such therapies have revolutionised the treatment of patients with a variety of advanced cancers, including metastatic melanoma (**Fig. 1**). 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, **identifying a pressing need to discover new and mechanistically distinct immunoregulatory mechanisms to drive advances in cancer and inflammatory disease immunotherapy**.

## Research themes
### Mechanisms of regulatory T (Treg) cell development and function

**Regulatory T (Treg) cells are rare immune cells with powerful suppressive functions**. Loss of 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. 2**).
**Regulatory T (Treg) cells are rare immune cells with powerful suppressive functions**. Loss of 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. 2**).
<div style="text-align:center">
<figure style="width:90%; min-width: 350px; display: inline-block; float:none; vertical-align: top; clear: both;">![Immunoregulatory function within the T cell lineage.]({{ site.url }}{{ site.baseurl }}/images/respic/treg_development.png)
<figcaption><b>Figure 2. Regulatory T cell development.</b> 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.
</figcaption></figure>
</div>

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.
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 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 expression marks Treg cells with highly suppressive function in tumours but that it is dispensable for their accumulation and suppressive function (Immunology 2021).

### Mechanisms of T cell maintenance and memory
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 developing **clinical collaborations** to determine the consequences of this for inflammatory and allergic diseases and cancer.
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.
<div style="text-align:center"><figure style="width:80%; min-width: 350px; display: inline-block; float:none; vertical-align: top; clear: both;">
![Functions of Bach2 in Treg development and maintenance.]({{ site.url }}{{ site.baseurl }}/images/respic/Bach2_Treg_maintenance_cropped.png)
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<b>Figure 3. Long-term maintenance of Treg responses requires quiescent Bach2-expressing cells. </b>
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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 have 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).
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).

### Molecular and cellular mechanisms of tumour immunosuppression

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. 4**). 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.
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. 4**). 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.

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<figure style="width:90%; min-width: 350px; display: inline-block; float:none; vertical-align: top; clear: both;">![How is the function of the immune system suppressed during tumour development?]({{ site.url }}{{ site.baseurl }}/images/respic/cancer_development.png)
<figcaption><b>Figure 4. Phases of tumour development according to the cancer immunoediting hypothesis.</b> 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.
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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. We are examining the **evolutionary 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 utilising **high-throughput CRISPR-based functional genetics** approaches to identify novel immunoregulatory mechanisms operating within the tumour microenvironment.
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. We are examining the **evolutionary 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 utilising **high-throughput CRISPR-based functional genetics** approaches to identify novel immunoregulatory mechanisms operating within the tumour microenvironment.

We have a long-standing interest in tumour immunity. 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 showed that **CCR8 marks Treg cells with highly suppressive function within tumours**, but is dispensable for their accumulation and function (Immunology 2021). We have productive industrial collaborations with GSK, F-Star Biotechnology and CRUK Therapeutic Discovery Laboratories.
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