Joke den Haan


Joke den Haan is associate professor in cellular immunology with a specific interest in the role of myeloid cells in adaptive immunity. She obtained her PhD from the University of Leiden in 1997 on the biochemical characterization of human minor histocompatibility antigens (cum laude) and did a post-doc at the University of Washington, Seattle, in the lab of Prof.dr. Mike J. Bevan on antigen cross-presentation by dendritic cell subsets (1998-2003). She joined the department of Molecular Cell Biology and Immunology in 2004 and her lab investigates the function of different types of macrophages and DCs subsets and develops cancer vaccines that specifically deliver antigens to these cell types to achieve optimal adaptive immune responses.

Research Line

Function of CD169-expressing macrophages and dendritic cells

CD169+ macrophages are localized at the marginal zone of the spleen and the subcapsular sinus of lymph nodes where they capture pathogens and extracellular vesicles. We have previously shown that antigens that are bound by splenic CD169+ macrophages are presented to B cells and transferred to cross-presenting dendritic cells that activate CD8+ and CD4+ T cell responses. We investigate the interactions of CD169+ macrophages with dendritic cells and other immune cells.

Figure 1. Mouse spleen with B cells in blue, red pulp macrophages in red and CD169+ macrophages in green.

Recently, a CD169-expressing Axl+ dendritic cell subset was discovered in human PBMC.  We can detect this cell type in healthy individuals and cancer patients and discovered that liposomal nanovaccines that bind to CD169 on these cells are taken up and presented to T cells.

Figure 2. Unsupervised tSNE analysis of dendritic cell subsets in human PBMC including CD169-expressing Axl+ DCs. (Affandi en al. PNAS 2020)

Development of cancer nanovaccines

We have generated different types of nanovaccines that target cancer antigens and adjuvant specifically to CD169+ macrophages and dendritic cells in mice and men. For this we utilize CD169-specific antibodies that are conjugated to cancer antigens in the form of proteins or peptides. In addition, we have generated liposomes that contain physiological ligands for CD169 to target cancer antigens and adjuvant to CD169+ macrophages and dendritic cells. Current studies are focused on the type of adjuvant and antigen to be included for optimal immune responses. In addition, we are generating nanobodies for human CD169 and will include them in differnet types of nanovaccins.

Figure 3. Outgrowth of melanoma tumor after vaccination with cancer antigen protein or peptide targeted to CD169+ macrophages (from van Dinther et al. 2018 Front in Immunol. 9: 1997)

Key publications

1.      Affandi, A.J., Olesek, K.,  Grabowska,J.  Nijen Twilhaar, M.K. Rodrıguez, E., Saris, A. Zwart, E.S., Nossent, E.J., Kalay, H. de Kok, M.,  Kazemier, G., Stöckl, J., van den Eertwegh, A.J. M.,  de Gruijl, T.D.,  Garcia-Vallejo, J.J., Storm, G., van Kooyk, Y., and J. M. M. den Haan 2021. CD169 Defines Activated CD14+ Monocytes With Enhanced CD8+ T Cell Activation Capacity. Frontiers in Immunology. doi: 10.3389/fimmu.2021.697840

2.      Grabowska J, Affandi AJ, van Dinther D, Nijen Twilhaar MK, Olesek K, Hoogterp L, Ambrosini M, Heijnen DAM, Klaase L, Hidalgo A, Asano K, Crocker PR, Storm G, van Kooyk Y, den Haan JMM. 2021. Liposome induction of CD8(+) T cell responses depends on CD169(+) macrophages and Batf3-dependent dendritic cells and is enhanced by GM3 inclusion. J Control Release 331:309-320.

3.      Grabowska J, Stolk DA, Nijen Twilhaar MK, Ambrosini M, Storm G, van der Vliet HJ, de Gruijl TD, van Kooyk Y, den Haan JMM. 2021. Liposomal Nanovaccine Containing alpha-Galactosylceramide and Ganglioside GM3 Stimulates Robust CD8(+) T Cell Responses via CD169(+) Macrophages and cDC1. Vaccines (Basel) 9.

4.      Nijen Twilhaar MK, Czentner L, Grabowska J, Affandi AJ, Lau CYJ, Olesek K, Kalay H, van Nostrum CF, van Kooyk Y, Storm G, den Haan J.M.M. 2020. Optimization of Liposomes for Antigen Targeting to Splenic CD169(+) Macrophages. Pharmaceutics 12       

5.      Affandi AJ, Grabowska J, Olesek K, Lopez Venegas M, Barbaria A, Rodriguez E, Mulder PPG, Pijffers HJ, Ambrosini M, Kalay H, O'Toole T, Zwart ES, Kazemier G, Nazmi K, Bikker FJ, Stockl J, van den Eertwegh AJM, de Gruijl TD, Storm G, van Kooyk Y, den Haan JMM. 2020. Selective tumor antigen vaccine delivery to human CD169(+) antigen-presenting cells using ganglioside-liposomes. Proc Natl Acad Sci U S A 117:27528-27539. We show in this paper that liposomes that contain gangliosides can bind to human CD169+ dendritic cells and are presented to T cells.

6.      van Dinther, D., H. Veninga, S. Iborra, E. G. F. Borg, L. Hoogterp, K. Olesek, M. R. Beijer, S. T. T. Schetters, H. Kalay, J. J. Garcia-Vallejo, K. L. Franken, L. B. Cham, K. S. Lang, Y. van Kooyk, D. Sancho, P. R. Crocker, and J. M. M. den Haan. 2018. Functional CD169 on Macrophages Mediates Interaction with Dendritic Cells for CD8+ T Cell Cross-Priming. Cell Rep 22: 1484-1495. In this paper we describe that CD169 enables adhesion and antigen transfer to cross-presenting dendritic cells and that DNGR-1 mediated activation stimulates cross-presentation.  PMID: 29425504

7.      Veninga, H., E. G. Borg, K. Vreeman, P. R. Taylor, H. Kalay, K. Y. van, G. Kraal, L. Martinez-Pomares, and J. M. den Haan. 2015. Antigen targeting reveals splenic CD169 macrophages as promoters of germinal center B-cell responses. Eur. J. Immunol 45: 747-757. In this paper we show that antigen targeting to CD169+ macrophages stimulates strong germinal center B cell responses and that CD169+ macrophages retain intact antigen on their surface for two days. PMID: 25487358

8.      Backer, R., T. Schwandt, M. Greuter, M. Oosting, F. Jungerkes, T. Tuting, L. Boon, T. O’Toole, G. Kraal, A. Limmer, and J. M. den Haan. 2010. Effective collaboration between marginal metallophilic macrophages and CD8+ dendritic cells in the generation of cytotoxic T cells. Proc. Natl. Acad. Sci. U. S. A 107: 216-221. This is our first paper showing that antigens are transferred from CD169+ macrophages to cross-presentation DCs for CD8+ T cell activation. PMID: 20018690

9.      den Haan, J. M., S. M. Lehar, and M. J. Bevan. 2000. CD8(+) but not CD8(-) dendritic cells cross-prime cytotoxic T cells in vivo. J. Exp. Med 192: 1685-1696. This paper is the first demonstration that CD8+ DCs (currently named cDC1) selectively cross-present cell-associated antigens. PMID: 11120766