R. (Ralph) Stadhouders, MSc, PhD

Molecular Immunology of the Lung 

Research in the Molecular Immunology of the Lung group aims to unravel the molecular circuits that underlie immune cell (dys)function, with a strong focus on chronic inflammatory diseases of the lung and (lung) cancer. To this end, we use a multi-disciplinary approach that combines classical immunology experiments and mouse models with state-of-the-art (spatial) omics technology and (epi)genome editing of primary human immune cells.

Description of Research Line

Dysfunctional cellular behaviour is a leading cause of disease. My group aims to uncover fundamental principles that shape cellular identity and exploit this knowledge therapeutically. More specifically, we focus on immune cells called lymphocytes: T cells that launch highly specific adaptive immune responses against foreign substances (‘antigens’) or malignant cells, but also innate lymphoid cells (ILCs) that respond to generic danger signals from their tissue environment. To adequately respond to the plethora of immunological challenges, lymphocytes need to undergo rapid and large-scale changes in gene expression, which requires flexible yet precise control of transcription. During this process, lymphocytes can also enter a dysfunctional state, which causes immune disease (e.g. allergies, autoimmunity) and allows cancer cells to evade immune destruction. However, the molecular circuits that controls lymphocyte responses in health and disease remain incompletely understood. My group combines systematic epigenomic analyses of primary cells with tissue spatial profiling technologies, rigorous immunological assays and (epi)genome editing approaches to dissect the molecular basis of lymphocyte (dys)function. For this, we use samples from patients with chronic inflammation (e.g. asthma) or cancer but also from mouse models that mimic these disorders.

Dr. Ralph Stadhouders is a molecular biologist and immunologist working at the Erasmus MC in Rotterdam, the Netherlands. He obtained his PhD with Prof. Frank Grosveld at the Erasmus MC, after which he moved to the Centre for Genomic Regulation in Barcelona for postdoctoral training with Dr. Thomas Graf. In 2017 he returned to the Erasmus MC to establish his own research line in molecular immunology at the Pulmonary Medicine department. His laboratory is focused on obtaining a better understanding of how immune cell activity is controlled at a molecular level, with an emphasis placed on identifying mechanisms and cell subsets associated with severe asthma or failing anti-tumour immunity. His group also has a special interest in the non-coding part of our genome, and how it contributes to shaping the identity and responsive potential of immune cells. Dr. Stadhouders’ laboratory has received support from the Dutch Research Council (ZonMW VIDI), the Dutch Lung Foundation (Longfonds) and the Dutch Cancer Society (KWF). 

Stikker B, Trap L, Sedaghati-Khayat B, de Bruijn MJW, van IJcken WFJ, de Roos E, Ikram A, Hendriks RW, Brusselle G, van Rooij J*^#, Stadhouders R*^#. Epigenomic partitioning of a polygenic risk score for asthma reveals distinct genetically driven disease pathways. European Respiratory Journal. 2024 PMID: 38901884. *Co-senior authors; ^#Corresponding author

Stikker BS, Hendriks RW^#, Stadhouders R*^#. Decoding the genetic and epigenetic basis of asthma. Allergy. 2023 PMID: 36727912. *Senior author; ^#Corresponding authors

van der Ploeg EK, Krabbendam L, Vroman H, van Nimwegen M, de Bruijn MJW, de Boer GM, Bergen IM, Kool M, Tramper-Standers GA, Braunstahl GJ, Huylebroeck D, Hendriks RW*, Stadhouders R*^#. Type-2 CD8+ T cell formation relies on the alarmin interleukin-33 and is linked to asthma exacerbations. Nature Communications. 2023 PMID: 37612281. *Co-senior authors; ^#Corresponding author

Onrust-van Schoonhoven A, de Bruijn MJW, Stikker B, Brouwer RWW, Braunstahl GJ, van IJcken WFJ, Graf T, Huylebroeck D, Hendriks RW, Stik G^#, Stadhouders R*^#. 3D chromatin reprogramming primes human memory Th2 cells for rapid recall and pathogenic dysfunction. Science Immunology. 2023 PMID: 37418545. *Senior author; ^#Corresponding authors

Cuartero S*^#, Stik G*^#, Stadhouders R*^#. Three-dimensional genome organization in immune cell fate and function. Nature Reviews Immunology. 2022 PMID: 36127477. *Co-senior authors; ^#Corresponding authors

van Krimpen A, Gerretsen VIV, Mulder EEAP, van Gulijk M, van den Bosch TPP, von der Thüsen J, Grünhagen DJ, Verhoef C, Mustafa D, Aerts JG^#, Stadhouders R*, Dammeijer F*. Immune suppression in the tumor-draining lymph node corresponds with distant disease recurrence in patients with melanoma. Cancer Cell. 2022 PMID: 35839777. *Co-senior authors; ^#Corresponding author

van der Ploeg EK, Golebski K, van Nimwegen M, Fergusson JR, Heesters BA, Martinez-Gonzalez I, Kradolfer CMA, van Tol S, Scicluna BP, de Bruijn MJW, de Boer GM, Tramper-Stranders GA, Braunstahl GJ, van IJcken WFJ, Nagtegaal AP, van Drunen CM, Fokkens WJ, Huylebroeck D, Spits H^#, Hendriks RW, Stadhouders R*^#, Bal SM*. Steroid-resistant human inflammatory ILC2s are marked by CD45RO and elevated in type 2 respiratory diseases. Science Immunology. 2021 PMID: 33514640. *Co-senior authors; ^#Corresponding authors

Research Highlight #1. We discovered that cytokine-driven chromatin re-wiring can generate a novel inflammatory group 2 ILC (‘ILC2’) subset that is resistant to corticosteroids - the mainstay treatment for chronic (lung) inflammation (PMID: 33514640). Indeed, we found these cells to be specifically associated with a severe disease course in asthma patients. Cytokine-mediated functional plasticity was also detected in CD8+ T cells from patients with severe asthma, endowing these cells with the pathogenic capacity to produce inflammatory mediators driving asthma (PMID: 37612281). These studies identified lymphocyte subsets linked to therapy-resistant severe immunopathologies, offering new targets for therapy development.

Research Highlight #2. Our recent work on adaptive immune responses showed that human memory T cells undergo 3D chromatin reprogramming in vivo to enable rapid reactivation (or ‘recall’) of the adaptive immune system (PMID: 37418545). Importantly, we provide evidence that this specific chromatin organization is improperly controlled in patients with chronic lung inflammation driven by memory T cells, connecting basic chromatin biology to the pathogenic dysfunction of lymphocytes.

Research Highlight #3. We have recently used spatial proteogenomics approaches to link immune suppression within tumour-draining lymph nodes to rapid metastatic disease recurrence in melanoma patients (PMID: 35839777). Importantly, we could demonstrate that lymphocyte dysfunction is highly dependent on spatial localization within tissues, emphasizing the need for in situ profiling in future studies of lymphocyte dysfunction – a concept we are currently actively pursuing.   

• Marjolein de Bruijn (technician)
• Menno van Nimwegen (technician)
• Dr. Esmee van der Ploeg (post-doc)
• Dr. Mieke Metzemaekers (post-doc)
• Dr. Niels Rinzema (post-doc)
• Anne Onrust – Van Schoonhoven (PhD candidate)
• Anneloes van Krimpen (PhD candidate)
• Bernard Stikker (PhD candidate)
• Simone Olsthoorn (PhD candidate)
• Lianne Trap (PhD candidate)
• Jochem Weekers (PhD candidate)