Professor by special appointment Chemical Immunology
Jacques Neefjes is a professor and head of the department of Cell and Chemical Biology. He is a member of the Raad voor Aard- en Levenswetenschappen of KNAW (RAL-KNAW), the Scientific advisory Board of the IMBC in Porto (Portugal), EMBO, the Faculty of 1000, the Award commitee Tom Voute prize, Review of the Board of the Swedish Academy, the Scientific Council Children Oncology (KiKa), and he is Chairman Mid-term reviews and meeting of KiKa grants. He is also ad hoc advisor for decision for tenured positions at Harvard Medical School, reviewing at ANR (France) and other international scientific bodies, and Ombudsman for Sanquin Amsterdam.
Jacques Neefjes is a professor and head of the department of Cell and Chemical Biology.
Cell and Chemical Biology
Research by Neefjes and his laboratory has centred on three major themes that connect to various NWA agenda points:
1. Antigen presentation by Class I and II MHC: MHC molecules are fundamental mediators of adaptive immunity, where class I MHC governs recognition of virus-infected and tumor cells by the immune system, while class II MHC instigates anti-bacterial responses and helps CTL activation. In this arena, Neefjes’ work has focused around the main theme of how MHC molecules acquire and display antigenic peptides to allow anti-viral and anti-tumor immune responses. Neefjes has elucidated many steps in these pathways, including the role of peptides in class I and II MHC transport and the identification of the transporter TAP that pumps peptides from the cytosol to class I MHC in the ER (which is targeted by viruses to avoid their presentation to the immune system). He developed technologies to visualize peptide products in living cells that were instrumental in the definition of so-called DRiPs—peptides originating from newly synthesized proteins—that were a conceptual breakthrough explaining how viral antigens are recognized almost immediately following infection onset. Building on these findings, Neefjes later showed that radiotherapy increases class I MHC expression and immune system responses against poorly immunogenic tumors, which he combined in radio-immunotherapy, presently explored in the clinic. Alongside these breakthroughs, Neefjes discovered the class II MHC compartment—an endosomal reservoir, wherein class II MHC molecules encounter antigenic peptides and become competent to trigger the immune response. He pioneered the use of GFP fusion proteins to reveal the molecular basis of control of endosomal movement and interrogate the cell biology of late endosomes and lysosomes. Through this work, Neefjes elucidated the molecular underpinnings of the disease phenotype found in Niemann-Pick patients and made fundamental discoveries of functional interactions between endosomes and the ER—a new conceptual paradigm of communication between organelles in cell biology.
2. Bacterial infections and cancer: Neefjes expanded his work on endosomes to the phagosome, where various pathogenic bacteria proliferate inside the host. Upon fusion of phagosomes with lysosomes, bacteria become degraded and presented to the immune system. Neefjes showed that bacteria, such as Salmonella and M. tuberculosis, activate host kinase AKT1, which prevents fusion and bacterial destruction. By combining chemistry, cell biology and biochemistry with genetic screens, Neefjes identified inhibitors to disturb this bacterial survival strategy and dampen proliferation of bacteria within the host. This was a conceptual breakthrough, representing the first antibiotics acting by targeting the host, rather than the pathogen. AKT1 is also activated in human tumors, and Neefjes demonstrated that when bacteria activate host signaling for their intracellular survival, they inadvertently promote carcinogenesis in the host, as demonstrated for Salmonella typhi and the induction of gallbladder carcinoma. This work was further expanded by epidemiological studies, showing the link between food poisoning by Salmonella enteritidis and development of colon cancer. Since bacterial infections can be controlled, their connections to cancer risk can now be translated into preventive measures.
3. Anthracyclines and the efficacy/side-effect puzzle: When testing chemical modulations of MHC antigen presentation, Neefjes explored one of the most used frequently used classes of anti-cancer drugs—the anthracyclines—which were long thought to act by generating DNA double stranded breaks. This ‘dogma’ failed to explain dramatic variation in clinical outcomes between structurally different anthracyclines. In a breakthrough study, Neefjes showed that some anthracyclines, can also generate chromatin damage by ejecting histones from DNA. Neefjes then used chemistry to synthesize ‘away’ the treatment-limiting side-effects of anthracyclines—namely, cardiotoxicity and secondary tumors. A variant chemotherapeutic drug called aclarubicin was identified by Neefjes as lacking these serious side effects, motivating him to bring together oncologists, chemists, pharmacists and fermentation experts to produce the basic compound (at clinical grade) for introducing aclarubicin into the clinic for the treatment of relapsed AML, which is projected to take effect in 2018, and other tumors.
Sjaak Neefjes absolved the study Chemistry at the Free University Amsterdam. He absolved his doctoral research at the Netherlands Cancer Institute (NKI) in Amsterdam. The title of his doctoral thesis (November 1990, cum laude) reads ‘Cell Biological Aspect of MHC class I and II molecules’. His career later on was as follows.
Post Graduate Education and Training
1991 Post-doctoral research with prof. dr. H.L. Ploegh, Division of Cellular Biochemistry, the Netherlands Cancer Institute, Amsterdam
1991-1992 Visiting scientist at the laboratory of drs. C. Benoit and D. Mathis at the Institut de Chimie Biologique, Strassbourg
1992-1993 EMBO long-term fellowship, laboratory of prof. dr. G Hämmerling at the Deutsche Krebs Forschungs Zentrum (DKFZ), Heidelberg
1993 – 1997 Staff member, Division of Cellular Biochemistry, the Netherlands Cancer Institute, Amsterdam
1998 – 2008 Head Division of Tumor Biology, the Netherlands Cancer Institute, Amsterdam
1999 – 2014 Extraordinary professor at Leiden University, chair of 'Antigen Presentation and Processing'
2000 – 2003 Dean Graduate School Oncology Amsterdam (OOA)
2007 – 2011 Deputy Scientific Director, the Netherlands Cancer Institute, Amsterdam
2009 – 2016 Head Division of Cell Biology II, the Netherlands Cancer Institute, Amsterdam
2009 – 2011 Visiting professor at the Centre for Immune Regulation of the University of Oslo, Norway
2009 – present Ombudsman for Sanquin Amsterdam
2014 – 2016 Extraordinary professor at Leiden University, chair 'Chemical Immunology'
2016 – 2017 Head Division of Chemical Immunology, LUMC, Leiden NL
2018 – present Head Department of Cell and Chemical Biology, LUMC, NL
Prizes and honourable appointments
Neefjes has obtained various awards throughout his career in different disciplines, including: the Antoni van Leeuwenhoek prize (1990), a Golden Medal of the Royal Dutch Chemical Society (KNCV; 1996), ERC Advanced grants (2009; 2015), Gravity grant ('Zwaartekrachtssubsidie'; 2015) and the career award of the Dutch Society of Immunology NVVI (the van Lochem lecture; 2015). He has also delivered two honorary lectures: the Ruysch lecture (AMC, Amsterdam; 2012) and The Beatty Lecture (McGill University, Montreal, Canada; 2012).
Other honours and awards:
1992 EMBO long term fellowship
1996 Pioneer Grant
2007 Elected member EMBO
2009 ERC Advanced Grant
2010 Elected member European Academy of Cancer Sciences
2013 Elected member Academia Europaea
2013 Recipient and main applicant Gravity Program Institute for Chemical Immunology ICI
2014 Elected member of the Norwegian Academy of Science and Letters (Det Norske Videnskaps-Akademi)
2015 Elected member and Dutch representative in the EU COST Scientific Committee
2015 Elected member of the Dutch Royal Society of Sciences and Arts (KNAW)
2015 van Loghem Lecture, the annual career award for research in Immunology from the Dutch Immunology Society NVVI
2016 Second ERC Advanced Grant
Local, national and international activities and responsibilities
2001 – present Scientific advisory Board of the IMBC in Porto, Portugal
2002 – 2005 Scientific Advisory Board Medical Research Council (MRC) UK
2002 – 2005 Scientific Council of the Veni Program of the Netherlands Scientific Organization (NWO)
2002 Scientific Council of the ZonMW/Diabetes Foundation
2003 – 2008 Scientific Council of the Netherlands Cancer Foundation KWF/ Wetenschappelijke Raad voor de Kankerbestrijding (WRK)
2007 – 2008 Chairman WRK
2005 Scientific Board TOP granting system, Chemical Sciences of the Netherlands Scientific Organization (NWO)
2007 – present EMBO member
2008 – 2013 CBG-CGC member
2009 – 2011 Deputy-chairman of the Scientific Council of the VIDI Program NWO
2009 – present Member Faculty of 1000
2009 – present Scientific Council Children Oncology (KiKa)
2010- 2011 Member of the Committee of Biosciences of the KNAW
2011 – 2015 Scientific Council Scientific Council Translational Research KWF
2011- Chairman Mid-term reviews and meeting KiKa grants
2011- Chairman Scientific Council Children Oncology (KiKa)
2012 Chairman Scientific Council of VIDI program NWO-CW
2013-2015 Member speerpunt Translationeel Onderzoek KWF
2013 Member NWO committee VICI grants
2013- Member Raad voor Aard- en Levenswetenschappen of KNAW (RAL-KNAW)
2014-Award commitee Tom Voute prize
2014-2018 Dutch representative in the research council EU COST program
2015 Chairman ALW Rubicon committee
2014 ANR LABEX jury, Paris
2015 president sub jury BIO MED Immunoinfection, Paris
2015- Review Board Swedish Academy
2015 Member NWO VICI committee
2015 Chairman Gravity Program Institute of Chemical Immunology
2016 ANR LABEX Jury Paris
2017 Chairman Scientific Committee European Immunology Meeting Amsterdam 2018
2018 Chairman site-visit committee HCERES Institutes Paris
1998 – 2016 Research council Netherlands Cancer Institute/Antoni van Leeuwenhoek (NKI/AVL)
2002 – 2005 Advisory Board Director of Science NKI/AVL
2007 – 2011 Deputy Director of Science NKI/AVL
Ad hoc advisor for decision for tenured positions at Harvard Medical School, reviewing at ANR (France) and other international scientific bodies
Current Grant Support (2016)
1. Title: ERC Advanced Grant Grant Agreement Number 249951 'MHC Class II-omics' Towards understanding and manipulation of MHC class II antigen presentation.
Date: 01-09-2010- 31-12-2014
Total grant period: € 2.080.000,00
2. Title: Systemic approach to define the MHC class I and II modifying secretome
Date: 01-11-2012- 01-11-2015
Total grant period: € 249.999,99
3. Title: Defining personalized treatment options for mesothelioma patients.
Date: 01-04-2013 - 01-04-2014
Sponsor: AVLKRF (KWF)
Total grant period: € 94.000,00
4. Title: Chemical Immunology to modulate cross-presentation for improved vaccines.
Date: 01-07-2013- 01-07-2017
Sponsor: NWO Chemische Wetenschappen
Total grant period: € 390.000,00
5. Title: Salmonella infections and gallbladder cancer.
Date: 01-09-2013 - 01-09-2017
Total grant period: € 550.800,00
6. Title: ERC Adv Grant ER control of endosomal positioning
Total grant period: €2.200.000,00
7. Title: Oncology research
Total grant period: €2.500.000,-
8. The Institute for Chemical Immunology
Sponsor: The ministery of Education and Sciences
Role: Chairman of the consortium
Total grant period: €17.000.000,00 (for chair about €1.000.000,-)
9. Title: Bacterial food poisoning and colon cancer; a cell biological and epidemiological study
Date: 01-11-2017 – 01-11-2021
Total grant period: €571.699,00
10. Title: Reintroducing aclarubicin in the treatment of relapsed and refractory AML patients
Date: 01-07-2018 – 01-07-2021
Total grant period: €1.210.700,00
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