Postdoc position available: development of immune-niche targeting therapeutics

BACKGROUND:

Approximately 50% of all human colorectal tumors develop distant metastases. Surgery for metastatic disease remains the only hope for cure. Systemic therapies, including chemotherapy and EGFR- and VEGF targeting antibodies have prolonged median overall survival to approximately 2 years, but have little effect on long-term survival. Immune checkpoint inhibitors are currently being tested for their therapeutic value and are expected to improve long-term survival. Such therapies may also be effective in other subtypes, possibly as part of combination treatment strategies. Unfortunately, the immune-suppressive activity of tumor-associated Treg cells represents a major hurdle for effective antitumor immunity, but highlighting their potential as an immunotherapeutic target. For this reason, there is considerable interest in the possible synergistic opportunities of combining Treg cell-targeted therapies with other modalities, such as immune checkpoint blockade, immune agonists, tumor-specific vaccines, radiotherapy, and chemotherapy. However, increased knowledge into mechanisms underlying Treg accumulation, function, and their role in metastasis and therapy resistance needs to be gained before such approaches can be clinically tested. Rational design of such strategies in CRC requires a thorough understanding of the tumor-immune niche, and in particular the role of T regulatory (Treg) cells which is currently lacking. Here, through the isolation and characterization of CRC-associated Treg cells together with the development and application of novel organoid based in vitro model systems for studying Treg cell-tumor interactions, we will advance our understanding of the tumor-immune niche. This information can be used to test and develop novel treatment strategies against CRC tumors. A major aim of the work is to translate fundamental research results into clinically useful tools and novel therapeutic strategies.

DEPARTMENT:

This project is part of a collaborative venture between the labs of Prof. Paul Coffer and Prof. Onno Kranenburg at UMC Utrecht together with Genmab BV. The successful candidate will be primarily based in the Coffer Lab, part of the Center for Molecular Medicine (CMM). Over the last decade, the Coffer group has developed considerable expertise in isolating, manipulating and characterizing both murine and human Treg cells. Work in the Kranenburg group is focused on metastatic colorectal cancer, aiming to obtain insight into the metastatic process and developing anti-metastatic therapeutic strategies. Genmab is an international biotechnology company specializing in the creation and development of differentiated antibody therapeutics for the treatment of cancer. The strong research experience between UMC Utrecht and Genmab BV will combined to characterize regulatory T cells in metastatic colorectal cancer (CRC). Together the combined experience in studying both immune cells and tumor biology, technologies and expertise will allow the project goals to be realized.

YOUR PROFILE:

You have a PhD in biomedical science, affinity with immunology and molecular-cell biology, and thrive in a dynamic and multidisciplinary research environment. In addition, you are motivated, creative and hard-working, with good organization and management skills, interested to work between groups at the UMC Utrecht and Genmab BV in the development of immune-niche targeting therapeutics. This position is also supported by a full-time technician.

CLICK HERE TO APPLY

If you have any questions about this vacancy, please contact me at: pcoffer@umcutrecht.nl

1 LIKES

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.

Regulation of oligodendrocyte differentiation by SOX4

SOX4 has been shown to promote neuronal differentiation both in the adult and embryonic neural progenitors. Ectopic SOX4 expression has also been shown to inhibit oligodendrocyte differentiation in mice, however the underlying molecular mechanisms remain poorly understood. Here we demonstrate that SOX4 regulates transcriptional targets associated with neural development in neural stem cells (NSCs), reducing the expression of genes promoting oligodendrocyte differentiation. SOX4 levels decreased during oligodendrocyte differentiation in vitro while SOX4 knockdown induces increased oligodendrocyte differentiation. Conversely, conditional SOX4 overexpression decreases the percentage of maturing oligodendrocytes, suggesting that SOX4 inhibits maturation from precursor to mature oligodendrocyte. We identify the transcription factor Hes5 as a direct SOX4 target gene and we show that conditional overexpression of Hes5 rescues the increased oligodendrocyte differentiation mediated by SOX4 depletion in NSCs. Taken together, these observations support a novel role for SOX4 in NSC by controlling oligodendrocyte differentiation through induction of Hes5 expression. This work was performed by Luca Braccioli as part of his thesis project in the Coffer Lab and has been published in Stem Cell Reports.