Welcome new PhD student Ed Corrigan

Ed Corrigan graduated from University of Maastricht before completing a Masters in Cancer, Stem Cells & Developmental Biology from Utrecht University. He has recently joined the Coffer Lab to work on a project focusing on understanding the biology and function of CD4+ effector T (Teff) cells in Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disease affecting up to 1/1000 children in Western countries. Like many autoimmune diseases, it is caused by a loss of tolerance whereby inappropriately active T lymphocytes (T cells) in the joint help to generate a perpetuating inflammatory environment. One critical control mechanism that ensures that peripheral T cells avoid inappropriate activation is the induction of anergy. Anergy is defined as a state of unresponsiveness induced by suboptimal T cell stimulation from engagement of the T cell receptor (TCR) in the absence of co-stimulation. TCR activation without co-stimulation leads to a hyporesponsive state termed anergy, where cells not proliferate or produce cytokines, and are resistant to subsequent stimulation. Recent studies have expanded our understanding of the complex set of inputs that T cells integrate to determine their fate and engage in effector functions or become anergic. Interestingly, we have found that T cells isolated from the synovial fluid of JIA patients are resistant to anergy. In collaboration with the Macian Lab (Albert Einstein, NYC) we are the first to show a connection between autophagy and anergy. Whereas T cells that are allowed to induce autophagy become activated and primed to respond to subsequent stimulations, cells where activation-induced autophagy is prevented become anergic and show markedly reduced responses to re-stimulation. Importantly, inhibition of autophagy during T cell activation can lead to an ‘anergy-like’ long-lasting state of hyporesponsiveness.

In this project Ed will be examining the link between resistance to anergy and autophagy in JIA T cells, and evaluating relevance for disease pathogenesis and therapeutic intervention.

This work is supported by a grant from the Dutch Arthritis Foundation.

Welcome new postdoc Nader Atlasy

Nader Atlasy has recently finished a PhD in Henk Stunnenberg’s lab at Radboud MC.. He has joined the Coffer Lab to work on a collaborative project together with Onno Kranenburg and Genmab bv focusing on understanding the biology and function of regulatory T (Treg) cells in colorectal cancer (CRC).

The immune compartment of the tumor microenvironment has recently attracted extensive interest due to its importance both in the understanding of basic tumor biology and implications for clinical applications. Importantly, the Immune Score (IS) that assesses immune infiltrate, has been shown to provide high prognostic value for certain cancer types. For example, when compared to other clinical criteria, the IS of both primary tumors and metastases was shown to be a better predictor of disease recurrence and survival in colorectal cancer patients following surgery. From a functional perspective, one of the key features of the tumor-immune contexture is its immunosuppressive environment, which underlies the basis for tumor escape from host immune destruction. While both tumor-intrinsic and -extrinsic mechanisms have been explored, it is now generally accepted that FOXP3+ T regulatory (Treg) cells, a small subpopulation of CD4+ T cells endowed with potent suppressive capacity, can play a pivotal role in inducing tumor-specific immune tolerance. Colorectal cancer (CRC) is diagnosed over 1.5 million worldwide each year and is the third most common cause of cancer-related mortality (700,000 CRC-related deaths per year). Mortality is almost invariably due to the development of distant metastases and the factors that determine whether or not a tumor will metastasize are poorly understood and an area of intense investigation. Sonia will be exploring the identity of CRC tumor-associated immune cells and the functional consequences of interactions between Treg cells and CRC tumors using a variety of state-of-the-art in vitro and in vivo tumor-organoid models.

Welcome new PhD student Sonia Arístin

Sonia Arístin graduated from Universidad de Alcalá (Madrid, Spain) before completing a Masters in Biomedical Sciences (Oncology track) from University of Amsterdam (UvA). She has recently joined the Coffer Lab to work on a collaborative project together with Onno Kranenburg focusing on understanding the biology and function of regulatory T (Treg) cells in colorectal cancer (CRC).

The immune compartment of the tumor microenvironment has recently attracted extensive interest due to its importance both in the understanding of basic tumor biology and implications for clinical applications.  Importantly, the Immune Score (IS) that assesses immune infiltrate, has been shown to provide high prognostic value for certain cancer types.  For example, when compared to other clinical criteria, the IS of both primary tumors and metastases was shown to be a better predictor of disease recurrence and survival in colorectal cancer patients following surgery. From a functional perspective, one of the key features of the tumor-immune contexture is its immunosuppressive environment, which underlies the basis for tumor escape from host immune destruction. While both tumor-intrinsic and -extrinsic mechanisms have been explored, it is now generally accepted that FOXP3+ T regulatory (Treg) cells, a small subpopulation of CD4+ T cells endowed with potent suppressive capacity, can play a pivotal role in inducing tumor-specific immune tolerance. Colorectal cancer (CRC) is diagnosed over 1.5 million worldwide each year and is the third most common cause of cancer-related mortality (700,000 CRC-related deaths per year). Mortality is almost invariably due to the development of distant metastases and the factors that determine whether or not a tumor will metastasize are poorly understood and an area of intense investigation. Sonia will be exploring the functional consequences of interactions between Treg cells and CRC tumors using a variety of state-of-the-art in vitro and in vivo tumor-organoid models.

This work is supported by a grant from World Wide Cancer Research.

A druggable Foxp3 stability circuit that can fine-tune immune homeostasis

The Foxp3 transcription factor is a crucial determinant of both regulatory T (Treg) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires the tight regulation of Foxp3 transcriptional output, and this involves both transcriptional and post-translational regulation. Here, we show that during T cell activation, phosphorylation of Foxp3 in Treg cells can be regulated by a TGF-β activated kinase 1 (TAK1)-Nemo-like kinase (NLK) signaling pathway. NLK interacts and phosphorylates Foxp3 in Treg cells, resulting in the stabilization of protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase. Conditional Treg cell NLK-knockout (NLKΔTreg) results in decreased Treg cell-mediated immunosuppression in vivo, and NLK-deficient Treg cell animals develop more severe experimental autoimmune encephalomyelitis. Our data suggest a molecular mechanism, in which stimulation of TCR-mediated signaling can induce a TAK1-NLK pathway to sustain Foxp3 transcriptional activity through the stabilisation of protein levels, thereby maintaining TREG cell suppressive function. This work is a collaborative effort between our group and Dietmar Zaiss and has been driven by Veerle Fleskens (UMCU) and Carlos Minutti (University of Edinburgh) together with many important international partners. Part of a long-term research line we have identified a druggable Foxp3 stability circuit that could be used to modulate Treg cell activity in a variety of pathological situations. You can read more about this work here in Cell Reports.

Welcome to new PhD student Alessandro Cutilli

Alessandro Cutilli recently graduated from University of Padua (Italy) and has joined the Coffer Lab to work on a collaborative project together with Caroline Lindeman’s group focusing on CD4+ T cells in graft-versus-host-disease. Graft-versus-Host-Disease is the most life-threatening complication following allogeneic hematopoietic stem cell transplantation (HSCT) where patients are transplanted with a combination of donor hematopoietic stem cells and lymphocytes. Despite treatment and prevention strategies GvHD with intestinal and liver involvement still has around a 30% mortality rate and forms a large urgent unmet medical need. Transferred alloreactive T cells respond in a complex manner, and the reasons for induction of GvHD, while involving inappropriately targeted CD4+ T cell activation, remain largely unclear and difficult to predict. Devising strategies to transiently "inactivate" T cells that mediate unwanted immune responses will have important implications for the control GvHD after bone marrow transplantation. Existing therapies, such as steroid-treatment, tend to broadly suppress undesirable immune responses, are often ineffective, and can trigger a variety of unwanted side effects. This is particularly dangerous in transplant patients who are extremely susceptible to infection. One critical control mechanism that ensures peripheral T cells avoid inappropriate activation is the induction of anergy, a hyporesponsive-state where cells don’t proliferate or produce cytokines and are more resistant to subsequent stimulation. Our recent preliminary data has shown for the first time that it is possible to induce anergy in CD4+ T cell populations by inhibiting (macro)autophagy, even in hyperactivated cells. Alessandro will be further investigating this using complex in vitro 3D cell culture systems as part of the EU COFUND RESCUE consortium.

PhD survivor! Congratulations Dr. Janneke Peeters

Congratulations to Dr. Janneke Peeters who has successfully defended her PhD thesis entitled: “Transcriptional and epigenetic mechanisms underlying autoimmune diseases”.

Autoimmune diseases are complex and the various molecular mechanisms that contribute to autoimmune pathogenesis as still poorly understood. The work described in Janneke’s thesis is aimed to create insight into molecular mechanisms underlying autoimmune disease, focusing on epigenetic regulation and autophagy. These studies provide novel insight into transcriptional and epigenetic mechanisms in an autoimmune disease setting and demonstrate that altered enhancer regulation and autophagy is associated with autoimmunity. Furthermore, these findings indicate that targeting these molecular mechanisms might be of interest for the treatment of autoimmune diseases.

Janneke will soon be starting a postdoc position at University of California Berkeley with Dr. Michel DuPage where she will be utilizing sophisticated genetic tools to modify T cells and tumor cells in the context of pre-clinical cancer models.

Dutch Arthritis Society project funded!

Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disease affecting up to 1/1000 children in Western countries. Like many autoimmune diseases, it is caused by a loss of tolerance whereby inappropriately active T cells in the joint help to generate a perpetuating inflammatory environment. Peripheral tolerance mechanisms regulating T cell function are essential to maintain immune homeostasis, and their deregulation can result in autoimmunity. Our unpublished observations demonstrate that effector T cells from the synovial fluid of JIA patients are resistant to induction of anergy, one of the peripheral mechanisms to maintain tolerance. Preliminary work by Enric Mocholi in the Coffer Lab has revealed that blocking autophagosome formation induces anergy in both peripheral blood healthy and JIA synovial fluid CD4+ T cells. We hypothesise that inhibition of autophagosome formation may provide a novel approach for controlling JIA, bearing in mind that this might also be applicable to other related (auto)immune diseases. With funding from ReumaNederland we are looking forward to taking this translatable work forward in 2019.

Transcriptional regulation of tumor-induced angiogenesis

The expression of the transcription factor SOX4 is increased in many human cancers, however, the pro-oncogenic capacity of SOX4 can vary greatly depending on the type of tumor. Both the contextual nature and the mechanisms underlying the pro-oncogenic SOX4 response remain unexplored. Here, we demonstrate that in mammary tumorigenesis, the SOX4 transcriptional network is dictated by the epigenome and is enriched for pro-angiogenic processes. We show that SOX4 directly regulates endothelin-1 (ET-1) expression and can thereby promote tumor-induced angiogenesis both in vitro and in vivo. Furthermore, in breast tumors, SOX4 expression correlates with blood vessel density and size, and predicts poor-prognosis in patients with breast cancer. Our data provide novel mechanistic insights into context-dependent SOX4 target gene selection, and uncover a novel pro-oncogenic role for this transcription factor in promoting tumor-induced angiogenesis. These findings establish a key role for SOX4 in promoting metastasis through exploiting diverse pro-tumorigenic pathways. This work, pioneered by Stephin Vervoort, Olivier de Jong, Cindy Frederiks and Guy Roukens is a collaboration between many groups within The Netherlands and the United Kingdom and is published in eLife here.