M. (Mandy) van Gulijk, MSc, PhD

Cancer immunotherapy created a paradigm shift in the treatment of patients with cancer. However, the majority of treated patients does not respond durably or inevitably develops recurrence for reasons incompletely understood. We and others have shown that regulatory T cells are not mere bystanders but can be activated by immunotherapy that blocks PD-1 interactions with PD-L1, causing therapy resistance in the process. My current research focuses on how regulatory T cells are activated by immunotherapy to identify targets that could prevent or revert this undesirable mechanism. To this end, we use state-of-the-art techniques (including multi-color flow cytometry, cell sorting, single cell sequencing, ATAC sequencing) that are applied in both preclinical murine tumor models and patient-derived samples (including mesothelioma, lung cancer, pancreatic cancer and melanoma).

I obtained my MSc degree in Biomedical Sciences at Leiden University in 2018 and subsequently started as a PhD candidate at the laboratory of Pulmonary Medicine headed by Prof. Rudi Hendriks and Prof. Joachim Aerts, in collaboration with Prof. Thorbald van Hall (LUMC, Leiden). During my PhD trajectory, I focused on unraveling the prerequisites for effective anti-tumor immunity and the mechanisms behind resistance to immunotherapies, with a focus on immune checkpoint blockade and dendritic cell vaccination. In 2024, I defended my thesis entitled ‘En Pointe: Composing novel immunotherapy strategies to improve systemic anti-tumor immunity’ with honors and started as a postdoctoral researcher to continue my research lines, with a focus on the role of immunotherapy-activated regulatory T cells in therapy resistance. This project line has been awarded with research grants, including the ‘Mesothelioma Applied Research Grant’ (2022).

1. PD-L1 checkpoint blockade promotes regulatory T cell activity that underlies therapy resistance. Van Gulijk M, van Krimpen A, Schetters S, Eterman M, van Elsas M, Mankor J, Klaase L, de Bruijn M, van Nimwegen M, van Tienhoven T, van Ijcken W, Boon L, van der Schoot J, Verdoes M, Scheeren F, van der Burg SH, Lambrecht BN, Stadhouders R, Dammeijer F, Aerts J, van Hall T (2023). Sci Immunol. May 19;8(83):eabn6173.
2. Combination of PD-1/PD-L1 checkpoint inhibition and dendritic cell therapy in mice models and in patients with mesothelioma. Van Gulijk M, Belderbos B, Dumoulin D, Cornelissen R, Bezemer K, Klaase L, Dammeijer F, Aerts J. Int J Cancer. 2023
3. Immune suppression in the tumor-draining lymph node corresponds with distant disease recurrence in patients with melanoma. Van Krimpen A, Van Gulijk M, Gerretsen VIV, Mulder EEAP, van den Bosch TPP, von der Thüsen J, Grünhagen DJ, Verhoef C, Mustafa D, Aerts JG, Stadhouders R, Dammeijer F. Cancer Cell (2022)
4. Low-dose JAK3-inhibition improves anti-tumor T-cell immunity and immunotherapy efficacy. Dammeijer F, Van Gulijk M, Klaase L, van Nimwegen M, Bouzid R, Hoogendoorn R, Joosse M, Hendriks R, van Hall T and Aerts J Molecular Cancer Therapeutics (2022)
5. The PD-1/PD-L1-Checkpoint Restrains T cell Immunity in Tumor-Draining Lymph Nodes. Van Gulijk M, Dammeijer F, Mulder EE, Lukkes M, Klaase L, van den Bosch T, van Nimwegen M, Lau SP, Latupeirissa K, Schetters S, van Kooyk Y, Boon L, Moyaart A, Mueller YM, Katsikis PD, Eggermont AM, Vroman H, Stadhouders R, Hendriks RW, Thüsen JV, Grünhagen DJ, Verhoef C, van Hall T, Aerts JG. Cancer Cell (2020)
6. Combination Strategies to Optimize Efficacy of Dendritic Cell-Based Immunotherapy. Van Gulijk M, Dammeijer F, Aerts JGJV, Vroman H. Frontiers Immunology (2018)

We have recently demonstrated that ICB enhances the suppressive capacity of regulatory T cells, which is associated with treatment resistance. This has been shown in a wide variety of preclinical tumor models as well as in PBMCs and tumor biopsies of cancer patients. The current focus is to further delineate the effect of ICB on regulatory T cells with the goal to identify suitable targets for treatment that could prevent ICB-mediated regulatory T cell activation. This will ultimately result in enhanced efficacy of ICB. For this project, we closely collaborate with departments in LUMC and with the VIB in Ghent.

FIGURE 1 | Increased proliferation of PD-L+ regulatory T cells (Tregs) in peripheral blood after αPD-1/αPD-L1 treatment is associated with therapy resistance in non-small cell lung cancer (NSCLC) or mesothelioma