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Immunology: Ton Schumacher

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Ton Schumacher, Ph.D. professorGroup Leader

About Ton Schumacher

Research interest: Cancer Immunology

The aim of our research is straightforward 1). To design novel technologies that can be used to examine and modify antigen-specific T cell immunity 2). To use these tools to unravel and manipulate the molecular processes underlying immune recognition by T lymphocytes. Within these projects, a main focus is on the design and testing of novel concepts for adoptive immunotherapy of cancer.

Dissecting antigen-specific T cell immunity in human cancer

There is now substantial evidence that therapeutic manipulation of immune reactivity can result in clinically meaningful effects on human cancer. For example, T cell responses induced by T cell checkpoint blockade, or infusion of ex vivo expanded tumor-infiltrating T cells (TIL therapy), has shown substantial activity in metastatic melanoma. Importantly, at present it is largely unknown which cytotoxic T cell reactivities mediate such cancer regressions. Furthermore, knowledge of such reactivities would be of obvious use, both to monitor current therapies and to design more targeted strategies that selectively aim to enhance immune reactivity against these antigens.

To address this issue, we have developed a broadly applicable "MHC-based toolkit" for the parallel detection of many different T cell populations within a single sample. In many ongoing projects we are now using this platform to understand the effects of for instance TIL therapy and T cell checkpoint blockade in cancer patients. 

A particularly intriguing twist to this research line is the notion that mutated 'neo-antigens' that could serve as regression antigens in patients may be identified on the basis of cancer exome data. Towards this purpose, we generate maps of all tumor-specific mutations within human cancer lesions and use this information to analyze reactivity against predicted mutated peptides by T cells from the same patient.  Interestingly, the first evidence for the feasibility of this exome-based approach to identify human neo-antigens has recently been obtained. In the coming years, this approach should offer the possibility to determine to what extent the mutational landscape in human tumors is recognized by cytotoxic T cells. In addition, this link between cancer genomics and T cell immunology may allow one to address fundamental questions about cancer immune editing, and may suggest novel ways to harness the T cell repertoire in human disease.
 (Selected references: Toebes et al., Nat Med 2006; Hadrup et al., Nat Methods 2009, Heemskerk et al., EMBO J 2012, Kvistborg et al., Curr Opin Immunol 2013, van Rooij et al., J Clin Oncol 2013)

Dissection of cellular immunity through single cell tracing

To also allow the tracing of cell fate at the single cell level, we have developed technologies with which individual cells can be tagged with genetic barcodes. This tagging technology relies on the use of oncoretroviral and lentiviral libraries containing thousands of different DNA 'barcodes'. Infection of progenitor cells of interest by these libraries of viral vectors and subsequent analysis of the barcodes present within the cell populations that arise from them can then be utilized to reveal lineage relationships. In recent projects, we have for instance used this barcode labeling strategy, together with second generation sequencing, to measure the output of individual antigen-specific T cells, and to address which (types of) progeny are generated by individual multipotent hematopoietic progenitors in vivo. In addition to this in vivo single cell tracing work, we have become highly interested in a specialized subset of tissue-resident memory T cells. In recent work we have demonstrated the existence of a population of "skin patrolling memory T cells" that cruise through former sites of infection, and in ongoing work we are evaluating how this T cell population can form a possible link between renewed antigen production and the development of a state of 'pathogen alert'.

(Selected references: van Heijst et al., Science 2009; Schumacher et al., Nat Rev immunol 2010, Ariotti et al., PNAS 2012, Gerlach et al., Science 2013, Naik et al., Nature 2013) 

Adoptive T cell therapy (collaboration with Haanen lab)

The cornerstone of our translational work is the development and evaluation of adoptive T cell therapies for human cancer. The MHC-based monitoring strategies described above form a very useful starting point for the further clinical development of TCR engineered T cell therapy, an area of research that is of special interest to the lab. In the coming years we aim to prepare for a large clinical program in which we will test the clinical value of a series of different T cell receptors that target various tumor-associated antigens. Towards this goal, we have developed technology that allows rapid TCR gene identification from many samples, and have utilized it to isolate a library of TCR genes that target many different cancer/germline antigens. In parallel work, we aim to evaluate the potential of non-viral gene transfer strategies and would like to evaluate the potential of more personalized strategies for TCR gene therapy, in which the tumor-specific TCR repertoire of individual patients is harnessed.
(Selected references: Kessels et al., Nat Immunol 2001; Bendle et al., Nat Med 2010, Linnemann et al., Nat Med 2013)

Protocols

Generation of peptide MHC class I monomers and multimers through ligand exchange
Retroviral transduction of murine T cells
Spin-based transduction of human T cells

Co-workers

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Ferenc A. Scheeren, Dr.

Senior Postdoctoral fellow

Experience

I was trained in human B cell immunology at the NKI and AMC. As a KWF fellow I went to Stanford University (California USA) to work in the lab of Michael Clarke. He was the first to describe cancer stem cells in solid tumors (breast cancer). Currently I am doing my second part of my KWF fellowship in the department of Immunology.

The focus of my work is solid tumor heterogeneity, stemness and sterile inflammation, with the purpose to find new therapeutic targets.

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Telma Lança, Ph.D.

Postdoctoral fellow

Experience

I did my PhD in the lab of Bruno Silva-Santos, at the Molecular Medicine Institute, Lisboa, where I studied the immune responses of gd T cells to tumors. As a Postdoctoral fellow in the Schumacher lab, I am studying the role of different immunosuppressive molecules in melanoma recognition by T cells.

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Wouter Scheper, Dr.

Postdoctoral fellow

Experience

After completing a PhD in tumor immunology at the UMC Utrecht, I started working as a postdoc in the Schumacher lab in November 2014. Here, my research aims to (a) dissect the specificities and functionalities of tumor-infiltrating T cells, and (b) develop novel approaches for the production of highly tumor-reactive, patient-specific clinical T cell products.

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Kaspar Bresser

Ph.D. Student

Experience

During my bachelor's (HLO at the Hogeschool Leiden) and master's (Biomedical Sciences at the University of Amsterdam) programs I received training while working in multiple labs at the LUMC, NKI and Whitehead Institute. During these internships I worked on various projects in the fields of tumor immunology, gene regulation and bioengineering.

My current research focuses on two subjects. First, to dissect the recognition of tumor cells by T cells, mainly from the tumor cell perspective. Second, to develop and engineer systems that allow one to address various subjects in tumor biology and immunology.

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Feline Dijkgraaf, MSc

Ph.D. Student

Experience

After finishing the broad Bachelor Bèta-gamma, I enrolled in the Master Biomedical Sciences at the University of Amsterdam. During this training, I specifically focused on cancer immunology at various research institutes such as the University of Cambridge, UK, the Amsterdam Medical Center and finally the Netherlands Cancer Institute (NKI-AVL). 

Currently, I am working on a PhD-project in the stimulating work environment of the NKI-AVL, in which I aim to study the behavior of tissue-resident memory T cells using live imaging. 

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Lorenzo Fanchi, MSc

Ph.D. Student

Experience

I'm Lorenzo Fanchi, PhD student in the Schumacher lab. I graduated at Wageningen University specializing in Medical Biotechnology. After working for a year in vaccine technology at Crucell, I was looking for a new challenge and had the opportunity to start my PhD at the NKI. I'm particularly interested in translational research in the field of cancer immunotherapy, specifically the role and therapeutic application of T cells in tumor infiltrating lymphocytes (TIL).

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Mirjam Hoekstra, MSc

Ph.D. student

Experience

I studied Life Science (Bio-exact, BSc) and Immunology (MSc) at the University of Amsterdam. During my studies, I performed research internships at the Netherlands Cancer Institute, Utrecht University and Massachusetts Institute of Technology, focusing on innate and adaptive immunity.

I'm mostly interested in fundamental immunology, specifically the role of T cells in immune responses. I have been working in the Schumacher lab as a PhD student since February 2014, and my work focuses on the behavior of tissue-resident memory T cells in the skin and the development of (reporter) technologies to study this.

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Anne van der Leun, MSc

Ph.D. Student

Experience

After finishing my Master "Cancer Genomics and Developmental Biology" at Utrecht University, I joined the Schumacher and Zuur labs as a PhD student in June 2015. Here, my main focus is on the dissection of T cell reactivity in head and neck cancer. I aim to better understand the functionality of tumor infiltrating lymphocytes at the single cell level, with the ultimate goal to improve current immunotherapeutic approaches and make immunotherapy applicable to a broader range of tumor
types. 

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Logtenberg, Meike

Meike Logtenberg, MSc

Ph.D. Student

Experience

After finishing my Bachelor's degree at University College Utrecht, I enrolled in the 'Cancer, Stem Cells and Developmental Biology' Master program at the Utrecht University. During this program, I was trained at the Hubrecht Institute (Utrecht) and at the Centre of Stem Cells and Regenerative Medicine (London) in cancer and stem cell biology. I started my PhD at the group of Ton Schumacher in October 2015. I am interested in identifying and understanding tumor escape mechanisms from the immune system, and how these mechanisms can be targeted to improve effective tumor cell killing.

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Riccardo Mezzadra, MSc

Ph.D. Student

Experience

I got my master degree in Medical Biotechnology in Milan, Italy, with an experimental thesis aimed at exploring potential genotoxic risks associated with gene therapy.

After that I started my PhD in Ton Schumacher's lab, where I am mainly involved in the development of novel gene transfer system and novel receptors for lymphocyte gene modification.

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Ali Can Sahillioglu

Ph.D. Student

Experience

The rate of scientific progress is limited by scientists' imagination, and their research tools. My research interest is to develop novel methods for single cell tracing and then use these to reveal the underlying mechanisms of cellular heterogeneity in T-cell populations and cancer.

I received my B.Sc. and M.Sc. degrees from Bogazici University, Istanbul, and I have been working in the Schumacher Lab since October 2013.

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Slagter, Maarten

Maarten Slagter

Ph.D. Student

Experience

My training consisted of a Bsc in Biomedical sciences and a Msc in Bioinformatics & Systems Biology at the University of Amsterdam and VU University Amsterdam. The internships I did revolved around data analysis and mathematical modelling in various biological contexts: Huntington's disease, synthetic (prokaryotic) biology and GPCR signalling. My current goal is to improve our quantitative understanding of T-cell mediated tumor regression and its dependence on other cells/factors in the local microenvironment, by computational analysis of experimental data generated here at the NKI and elsewhere. Hopefully this will contribute to more effective T-cell based immunotherapeutic strategies.

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Marlous van den Braber

Technician

Experience

After finishing my bachelor's degree, I joined Ton Schumacher's group as a Technician. In my work I mostly focus on MHC multimer-based immune monitoring. This includes not only the production and extension of our MHC based toolbox but also the monitoring of immune responses in patients treated with cancer immunotherapy.

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Marjolein de Bruijn

Technician

Experience

After finishing my Bachelor (BASc), I started working as a technician in the group of Ton Schumacher with the main focus of my work at the project of my internship period. As part of my study 'Biology and Medical Laboratory Research' at the Hogeschool Leiden I was given the opportunity to do my internship at the NKI, where we investigated cell death mechanisms induced after T cell recognition.

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Daisy Philips, MSc

Technician

Experience

After finishing my Master at the Free University of Amsterdam, I started working as a technician in the group of Ton Schumacher. The main focus of my work is the immunomonitoring of patients who received immunotherapy. This involves the analysis of patient material by combinatorial coding for the detection of tumor reactive T cells and the analysis of patient material to assess the functionality of tumor reactive T cells.

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Mireille Toebes

Research Technician

Experience

In September 1996, I started as a technician in the lab of Ton Schumacher: setting up the lab was a challenging job. During the following years, I developed my own projects, specializing myself in protein biochemistry, and in particular MHC multimer-based  tools for immune monitoring (Toebes et al, Nat Med. 2006).  In addition to this work, currently  I am training and assisting technicians, post-docs and PhD students, and have collaborations with groups in other disciplines, such as chemistry. This variation makes this job exciting: I can express my creative mind.

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Jos Urbanus

Research Technician

Experience

In 2001 I joined the Schumacher lab as a technician and since then I worked on several challenging projects (not all of them equally successful). A large part of my job is to design constructs and cloning strategies, of which the creation of the barcode mouse certainly was the most ambitious cloning project I was ever involved in. At the moment I am also managing the barcode mouse project. Over the years I have acquired quite some experience in developing gene designs and am now helping out many people in their efforts (as a one-eyed king in the land of the blind..)

Most of all I like the diversity in the research projects and the great support there is among colleagues.

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Apriamashvili, G.

Georgi Apriamashvili

Master Student

Experience

The possibility to mobilizethe immune system for cancer treatment has gained enormous momentum in recent years and yielded impressive success stories. Under the supervision of Ali Can Sahillioglu I am working on possible improvements for cancer immunotherapy, which are needed to make the treatment more successful and bearable for patients.

 

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Kweekel, Chris

Chris Kweekel

Master Student

Experience

As a second year masters student at the University of Amsterdam, I aimed for a challenging internship at the NKI in the group of prof. Ton Schumacher. Under supervision of Lianne Kok, I'm studying the kinetics, differentiation and clonality of CD8+ T cells during an influenza infection using the DNA barcoding system.

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Lindenbergh, Pieter

Pieter Lindenbergh, BSc

Master Student

Experience

For my first master (History and Philosophy of Science, UU) I studied the relation between immunological and molecular cancer research from the 1980s until now. Taking the NKI as a case study, I employed anthropological and historical methods to identify how and why these two branches of cancer research converge over time. Currently I am doing my major internship for my second master (Cancer and Stem Cell Biology, UU). Together with my supervisor Telma Lança, I aim to study the contribution of the mutational load to a tumor's immunogenicity in vivo.  

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Engelfriet, Melanie

Melanie Engelfriet

Undergraduate student

Experience

I'm studying Biology and Medical Laboratory Research at the Hogeschool Leiden and doing a research internship at the NKI in the group of Ton Schumacher.  My work involves the synthesis of bi-specific antibodies to target tumor cells.

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Key publications View All Publications

  • Heterogeneous Differentiation Patterns of Individual CD8+ T Cells

    Science 2013 May 3;340(6132):635-9.

    Gerlach C, Rohr JC, Perié L, van Rooij N, van Heijst JW, Velds A, Urbanus J, Naik SH, Jacobs H, Beltman JB, de Boer RJ, Schumacher TN. et al.

    Link to pubmed
  • Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma

    J Clin Oncol. 2013 Nov 10;31(32):e439-42

    van Rooij1* N, van Buuren1* MM, Philips1 D, Velds2 A, Toebes1 M, Heemskerk1 B, van Dijk1 LJA, Behjati3 S, Hilkmann4 H, el Atmioui4 et al.

    Link to publication
 
 

Recent publications View All Publications

  • The branching point in erythro-myeloid differentiation.

    Cell. 2015 Dec 17;163(7):1655-62. doi: 10.1016/j.cell.2015.11.059.

    Perié L, Duffy KR, Kok L, de BoerRJ, Schumacher TN.

    Link to pubmed
  • Subtle CXCR3-dependent chemotaxis of CTLs within infected tissue allows efficient target localization.

    J Immunol. 2015;195:5285-95.

    Ariotti S, Beltman JB, Borsje R, Hoekstra ME, Halford WP, Haanen JB, de Boer RJ, Schumacher TN.

    Link to pubmed
 

Contact

  • Office manager

    Renske Muns-de Jong

  • E-mail

    rm.d.jong@nki.nl

  • Telephone Number

    +31 20 512 2055

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