Immunology: 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
(Selected references: Kessels et al., Nat Immunol 2001; Bendle et al., Nat Med 2010, Linnemann et al., Nat Med 2013)
- Joost Beltman, Dr.Senior postdoctoral fellow
- Telma Lança, Ph.D.Postdoctoral fellow
- Carsten Linnemann, MScPostdoctoral Fellow
- Leïla Perié, Dr.Postdoctoral Fellow
- Ferenc A. Scheeren, Dr.postdoctoral fellow
- Silvia Ariotti, MScPh.D. Student
- Marit van Buuren, MScPh.D. Student
- Feline Dijkgraaf, MScPh.D. Student
- Lorenzo Fanchi, MSc.Ph.D. Student
- Mirjam Hoekstra, MScPh.D. student
- Sander Kelderman, MDPh.D. Student
- Riccardo Mezzadra, MScPh.D. Student
- Ali Can SahilliogluPh.D. Student
- Maarten Slagter, MScPh.D. Student
- Noor BakkerTechnician
- Laura BiesResearch Assistant
- Laura van DijkTechnician
- Daisy Philips, MScTechnician
- Nienke van Rooij, MScResearch Assistant
- Mireille ToebesResearch Technician
- Jos UrbanusResearch Technician
- Maaike van Zon BScTechnician
Joost Beltman, Dr.
Senior postdoctoral fellow
Cell migration in the immune system can nowadays be directly observed by in vivo imaging. I have developed novel approaches to quantitatively analyse and model such dynamic imaging data, and applied this to data on lymphocyte migration, T cell-dendritic cell interactions, recruitment of T cells into the immune response and target cell killing by T cells. In the future I would like to quantitatively model the role of T cells in tumor regression. Currently I am also developing methods to analyse next generation sequencing data of 'DNA barcoded' mice to trace the progeny of single cells over time.
Telma Lança, Ph.D.
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.
Carsten Linnemann, MSc
Born in Germany, I started to study Biochemistry at University Bielefeld (Germany) in 2002. From 2004 onwards, I was a student fellow of the German Academic Foundation. In 2007, I obtained my diploma (cum laude) with specialisations in Immunology and Gene Technology. Afterwards, I joined Ton Schumacher's lab at the NKI-AVL for my PhD-research. Here, I have investigated TCR gene transfer as an engineering strategy for T cell immunity against cancer. From 2009-2011 I was a fellow of the Boehringer-Ingelheim PhD-fellowship program. Currently, I continue my scientific work with Ton Schumacher, focusing on the analysis of kinship and antigen-specificities of intratumoral T cell subsets.
Leïla Perié, Dr.
After completing an experimental PhD in Immunology, I share my time equally between modeling and experimental immunology. My joint appointment in the experimental group of Ton Schumacher and the theoretical group of Rob de Boer (Utrecht University) is supported by an Intra-European Marie Curie fellowship and a Young Researcher award from the Bettencourt Schueller foundation. I study the differentiation of immune cells, by both experimental and theoretical approaches. In particular, I use the cellular barcoding technology that was developed in the Schumacher Lab, with a focus on analyses of the hematopoietic tree.
Ferenc A. Scheeren, Dr.
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.
Silvia Ariotti, MSc
Following pathogen clearance, a pool of memory CD8+ T cells is formed that provides protection against renewed infection with the same pathogen, both in the lymphatic organs and in peripheral tissues. To understand how such tissue-resident CD8+ memory T cells help protect peripheral tissue, I am analyzing the behavior of skin-resident memory T cells by intravital microscopy. I have discovered that memory T cells continuously patrol in between skin cells to scan for renewed infection (Ariotti S et al, PNAS 109:48), and in more recent work I am analyzing by which mechanisms memory T cell activation protects the local tissue.
Marit van Buuren, MSc
I started in the lab of Ton in October 2010, after being trained as an Immunologist at the University of Utrecht. Within my research I focus on the interaction of CD8 T cells and tumours.
In my main project, I analyse whether tumour immunoediting - a process in which the immune system plays a role in tumour progression by selecting for tumour cells that are more capable to survive in an immunocompetent host - is involved in human cancer.
My scientific goal is to understand the role of T-cell reactivity against patient-specific antigens to form a basis to improve immunotherapy directed against such antigens.
Feline Dijkgraaf, MSc
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.
Lorenzo Fanchi, MSc.
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).
Mirjam Hoekstra, MSc
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.
Sander Kelderman, MD
After my medical studies I decided to do a PhD in the field of cancer immunology/immunotherapy. In my projects I focus on several aspect of the interplay between the immune system and cancer.
One aim is to generate more patient-specific cell products (in particular for metastatic melanoma patients) by selecting tumor-reactive T cells directed against shared or patient-specific mutated antigens.
Another challenge is to expand our current knowledge on the intrinsic anti-tumor effects of infiltrating T cells in other malignancies like ovarian and colorectal cancer. These findings will hopefully in the future lead to a broader applicability of immunotherapeutic strategies.
Riccardo Mezzadra, MSc
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.
Ali Can Sahillioglu
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.
Maarten Slagter, MSc
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.
I studied Biomolecular Sciences at the VU Amsterdam, with a specialization in Cell Biology. Currently, I work as a technician in the group of Ton Schumacher. Amongst my tasks are the production of therapeutic products at the GMP facility of the NKI (AmBTU), such as Tumor Infiltrating Lymphocytes (TIL) and TCR transduced lymphocytes. I also produce a vaccine of plasmid DNA for a phase I clinical trial. In addition, I am involved in several research projects that aim the optimization of these clinical trials.
I joined Ton Schumacher's lab initially for an internship during my studies in September 2008, and after that as a full time member of the group. I am mainly involved in the development and analysis of novel (gene-modified) T cell therapies in preclinical models.
Laura van Dijk
During my study, 'Biology en medical laboratory research' at Hogeschool Leiden, I got the opportunity to do my internship at the NKI, within the group of Ton Schumacher. After finishing my internship and study, I continued working in the Schumacher group as a technician. At this moment, I'm mainly working on projects related to the use of MHC molecules to understand T cell recognition in human cancer.
Daisy Philips, MSc
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.
Nienke van Rooij, MSc
My name is Nienke van Rooij and I work under supervision of Ton Schumacher and John Haanen. I perform part of my work within our GMP facility where I am involved in the production of TIL cell therapy products for melanoma patients, for a clinical trial that we recently started at the NKI-AVL. To better understand the reactivities of these TIL, I am also analyzing TIL products for recognition of patient-specific mutations, as identified by cancer exome sequencing.
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.
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.
Maaike van Zon BSc
I am active as a technician in the group of Ton Schumacher to help develop clinical trials of TCR gene therapy. In this process, T cells are genetically engineered to target tumor antigens.
My work involves both research (optimization of protocols) and the generation of cell products for clinical use, and the fact that my work brings research and clinical work together makes it really interesting and exciting.
Before joining the Schumacher lab, I worked as a technician in the electron microscopy group, where I performed research on the localization of different mycobacteria. Here I also performed my internship to obtain my bachelor's degree.
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.
Recent publications View All Publications
Anti-CTLA4 therapy selectively induces novel melanoma-reactive CD8 T cell responses
Science Transl. Med. In press
Kvistborg P, Philips D, Kelderman S, Hageman L, Ottensmeier C, Joseph-Pietras D, Welters MJP, van der Burg S, Kapiteijn E, Michielin O,...Read more
Skin-resident memory CD8+ T cells trigger a state of tissue-wide pathogen alert
Science in press
Ariotti S, Hogenbirk MA, Dijkgraaf FE, Visser LL, Hoekstra ME, Song JY, Jacobs H, Haanen JB, and Schumacher TNAbstract
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