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Antigen presentation and immunotherapy

Research lines

In October 2013, I was embedded as a new PI in the department of Immunopathology because of the technical and immunological connection with the running research lines. My group applies diverse skills in the fields of cell and molecular biology to unbiasedly discover new immune regulation of T cells e.g. through antigen presentation, and to detail novel opportunities for and expose risks of T-cell-based immunotherapeutic approaches.

Identification of the tight regulation of MHC class I antigen presentation

Antigen presentation by MHC class I molecules is tightly controlled, and many components of this pathway are known by now. Some people even assume that every component controlling antigen presentation by MHC class I molecules is known, but a proper genome-wide screen to identify all essential regulators of MHC class I was never performed. We exploited haploid genetic screening (in close collaboration with Dr. Thijn Brummelkamp) to identify new proteins involved in the MHC class I antigen presentation pathway. Practically all known key proteins popped up in the hitlist, but also potentially novel regulators that were validated using CRISPR/Cas9 mediated knockout. We are currently evaluating the function of this valuable set of novel players in the MHC class I antigen presentation pathway. We do this using state-of-the-art genetic modification technology in combination with flow cytometry and by assaying tumor cell and T cell co-cultures.

We further apply our extensive genome-editing knowledge to perform CRISPR/Cas9 knockout experiments and screens to answer several important questions related to inflammation (collaboration with Dr. Ilse Jongerius) and transfusion-related anemia (collaboration with Dr. Ellen van der Schoot).

Secretome screening for T cell differentiation

Using a large cDNA expression library for secreted proteins (which we like to refer to as the secretome), we are searching for soluble factors capable of altering T cell differentiation. Changes in T cell differentation and function are evaluated by flow cytometry after short term culture (2 weeks). Next, we are trying to understand which impact the hits from this screen can have on improving anti-tumor T cell immunity. We consider this fundamental research as an elementary starting point for defining novel pathways of immune activation and inhibition.

We have validated our secretome screening pipeline by the identification of novel soluble factors that induce B cell differentiation (collaboration with Dr. Marieke van Ham) and others that inhibit viral entry and replication (collaboration with Dr. Matthijs Raaben).

 

Awards to members of the lab

  • May 2019: Robbert Spaapen received a NWO ZonMw Vidi grant for his research to the role glycolipids in cell-cell interactions during anti-cancer immune responses.
  • November 2018: Anastasia Xagara received an short-term EMBO fellowship to visit our lab for another three months.
  • August 2018: Twan de Waard received an EFIS-EJI ECI travel award to go to the European Congress of Immunology in Amsterdam.
  • April 2018: Twan de Waard received an EFIS-EJI travel award to go to the European Network of Immunology Institutes meeting in Sardinia, Italy.
  • June 2017: Twan de Waard received an EMBO travel award to go to the 9th International Workshop on Antigen Processing & Presentation in Salamanca, Spain.
  • June 2017: Marlieke Jongsma received an EMBO travel award to go to the 9th International Workshop on Antigen Processing & Presentation in Salamanca, Spain.
  • March 2016: Marlieke Jongsma received an short-term EMBO fellowship to visit the lab of Dr. Johannes Huppa  at the Medical University of Vienna for three weeks.
  • Sept 2015: Marlieke Jongsma received the in-house-seminar Award and has visited the lab of Dr. Justin Kline at the University of Chicago for two months in spring 2017.
  • June 2016: Robbert Spaapen received the Bas Mulder Award from KWF/Alpe d’HuZes.
  • April 2014: Together with Monika Wolkers, Derk Amsen, John Haanen and Daphne Thijssen-Timmer,  Robbert Spaapen acquired internal funding for cellular product & process development (PPOC).
  • July 2012: Robbert Spaapen received an NWO VENI grant.

Key publications

  • Identification of Minor Histocompatibility antigens based on the 1000 Genomes Project. Oostvogels R, Lokhorst HM, Minnema MC, van Elk M, van den Oudenalder K, Spiering E, Mutis T and Spaapen RM. Haematologica 2014 Dec
  • An ER-Associated Pathway Defines Endosomal Architecture for Controlled Cargo Transport. Jongsma ML, Berlin I, Wijdeven RH, Janssen L, Janssen GM, Garstka MA, Janssen H, Mensink M, van Veelen PA, Spaapen RM, Neefjes J. Cell. 2016 Jun 30;166(1):152-66.
  • Secretome Screening Reveals Fibroblast Growth Factors as Novel Inhibitors of Viral Replication. Van Asten SD Raaben M, Nota B and Spaapen RMJ Virol 2018 Jul
  • T cells specific for an unconventional natural antigen fail to recognize leukemic cells. Pont MJ, Oostvogels R, Van Bergen CAM, Van der Meijden ED, Honders MW, Bliss S, Jongsma MLM, Lokhorst HM, Falkenburg FJH, Mutis T, Griffioen M and Spaapen RM. Cancer Immunol Res 2019 Mar