Research

Understanding mechanisms of DC licensing and T-cell function in the tumor microenvironment

We study how dendritic cells (DCs), as key intermediaries between innate and adaptive immunity, regulate anti-tumor immune responses through antigen cross-presentation and control of T-cell activation, quality, and durability, and how these functions can be exploited to improve cancer immunotherapy. Our work focuses on classical type 1 DC (cDC1), a specialized DC subset with a strong capacity to cross-present cell-associated tumor antigens and prime cytotoxic T lymphocytes (CTLs). A central mechanistic interest is how CD4⁺ T-helper cells license DCs to sustain effective tumor-specific CTL responses within the tumor microenvironment (TME).

A major research line centers on investigating and validating DC-licensing programs and their impact on tumor-specific CD8⁺ T-cell immunity. Using in-depth bioinformatic analyses of clinical samples, together with conditioned in vitro human DC/T-cell co-culture platforms, we examine how DC-licensing shapes antigen cross-presentation, T-cell recruitment, and CTL effector differentiation. We identified a cDC1-licensing signature in human tumors that correlates with patient survival and responsiveness to PD1-targeted immune checkpoint blockade (ICI) and developed an in vitro human CTL priming platform based on licensed DCs that enables sensitive detection and functional characterization of tumor (neo)antigen-specific CD8⁺ T cells.

A further core interest of the group is the molecular biology of human DCs within the tumor TME, especially in patients who respond or fail to respond to ICI therapy. Using advanced single-cell RNA sequencing, spatial transcriptomics, and multiplex imaging, we dissect immune cell states, interactions, and spatial organization in human tumors. These approaches enable us to link DC-intrinsic pathways to immune activation or suppression, T-cell function or dysfunction, therapeutic enhancement or resistance, and clinical outcomes across tumor types.

Developing human translational models

Building on these mechanistic insights, we translate our understanding of DC-licensing into advanced experimental platforms for therapeutic development. Recognizing the central role of licensed cDC1 in driving robust CTL responses, we focus on improving human DC/T co-culture systems to allow reproducible functional interrogation. To overcome current limitations in primary cDC availability and genetic tractability, we are developing next-generation DC platforms based on engineered progenitor-derived cDCs and (non-)viral mRNA-based strategies for stable genetic modification. These approaches aim to enable durable modulation of DC function and scalable target validation of druggable receptor-ligand pathways for DC-centered cancer immunotherapies.

These platforms are further used to establish licensed DC/T coculture systems for the isolation and characterization of (neo)antigen-specific T-cell receptors targeting recurrent driver mutations (such as TP53, KRAS, NRAS, and FLT3). This work spans multiple cancer types, including melanoma, lung cancer, and acute myeloid leukemia, and supports the identification of functional tumor-reactive T cells with therapeutic potential.

With this focus, we integrate licensed DCs into three-dimensional (3D) and organ-on-chip tumor models, combined with spatially resolved technologies and functional immune assays, to enable mechanistic interrogation and identification of predictive biomarkers. These human-relevant platforms link licensed DC biology with tumor-associated immune suppression, including in uveal melanoma, and bridge fundamental DC biology with translational immunotherapy.

Ultimately, we aim to contribute to the development of next-generation, DC-centered immunotherapies that generate durable tumor-specific immune responses in patients who do not benefit from current treatments.

Key Publications

1. Lei X, de Groot DC, Welters MJP, de Wit T, Schrama E, van Eenennaam H, Santegoets SJ, Oosenbrug T, van der Veen A, Vos JL, Zuur CL, de Miranda NFCC, Jacobs H, van der Burg SH, Borst J, Xiao Y. CD4⁺ T cells produce IFN-I to license cDC1s for induction of cytotoxic T-cell activity in human tumors. Cell Mol Immunol. 2024 Apr;21(4):374-392. doi: 10.1038/s41423-024-01133-1. Epub 2024 Feb 21. PMID: 38383773; PMCID: PMC10978876.
   
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2. Lei X, Khatri I, de Wit T, de Rink I, Nieuwland M, Kerkhoven R, van Eenennaam H, Sun C, Garg AD, Borst J, Xiao Y. CD4⁺ helper T cells endow cDC1 with cancer-impeding functions in the human tumor micro-environment. Nat Commun. 2023 Jan 13;14(1):217. doi: 10.1038/s41467-022-35615-5. PMID: 36639382; PMCID: PMC9839676.
   
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3. Lei X, Wang Y, Broens C, Borst J, Xiao Y. Immune checkpoints targeting dendritic cells for antibody-based modulation in cancer. Int Rev Cell Mol Biol. 2024;382:145-179. doi: 10.1016/bs.ircmb.2023.07.006. Epub 2023 Aug 12. PMID: 38225102.
   
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4. Xiao Y, van Halteren AGS, Lei X, Borst J, Steenwijk E, de Wit T, Grabowska J, Voogd R, Kemps P, Picarsic J, van den Bos C, Borst J. Bone marrow-derived myeloid progenitors as driver mutation carriers in high- and low-risk Langerhans cell histiocytosis. Blood. 2020 Nov 5;136(19):2188-2199. doi: 10.1182/blood.2020005209. PMID: 32750121.
   
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5. Miao B, Hu Z, Mezzadra R, Hoeijmakers L, Fauster A, Du S, Yang Z, Sator-Schmitt M, Engel H, Li X, Broderick C, Jin G, Gomez-Eerland R, Rozeman L, Lei X, Matsuo H, Yang C, Hofland I, Peters D, Broeks A, Laport E, Fitz A, Zhao X, Mahmoud MAA, Ma X, Sander S, Liu HK, Cui G, Gan Y, Wu W, Xiao Y, Heck AJR, Guan W, Lowe SW, Horlings HM, Wang C, Brummelkamp TR, Blank CU, Schumacher TNM, Sun C. CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1. Cancer Cell. 2023 Oct 9;41(10):1817-1828.e9. doi: 10.1016/j.ccell.2023.08.008. Epub 2023 Sep 7. PMID: 37683639; PMCID: PMC11113010.
   
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6. Zhang X, McGinnis GS, Yu G, Chen S, Zheng P, Schürch CM, Hiam-Galvez KJ, Reticker-Flynn NE, Guo W, Yao W, Qiu J, Muselman AD, Linde IL, Hickey JW, Yan H, Tran VM, Qiu W, Brichart-Vernos D, Hirai T, Yu B, An X, Xiao Y, Paidassi H, Scharschmidt TC, Angelo M, Sheppard D, Chi H, Satpathy AT, Way S, Malissen B, Strober S, Engleman EG. Erythropoietin receptor on cDC1s dictates immune tolerance, Nature. 2025 accepted for publication

Collaborations

The Xiao group collaborates within the Immunology Department and with multiple departments across LUMC, integrating DC biology, tumor immunology, and translational cancer research. Within the department, we collaborate with Prof. Smits, Prof. Arens, Prof. Staal and Dr. de Kivit through joint projects and co-supervision of students and PhD candidates. Across LUMC, we work with Prof. Van der Burg, Dr. Welters, and Dr. Verdegaal (Department of Medical Oncology); Prof. Smit (Department of Pulmonary Diseases); Dr. Vu (Ophthalmology); Dr. Cohen, Dr. Verdijk, and Prof. de Miranda (Department of Pathology); and Dr. Griffioen (Department of Hematology). External collaborations include Prof. Schumacher (NKI), industry partners IMMIOS and MIMETAS, and international collaborators Dr. Sun (DKFZ), Prof. Garg (KU Leuven), and Dr. Zhang (Stanford University). Together, these partnerships ensure that mechanistic DC research is tightly connected to clinical application and immunotherapy development.