Paper: Chemotherapy induced intestinal damage directly modulates T cell behaviour

We have developed a human intestinal organoid-based 3D model system to study the direct effect of chemotherapy-induced intestinal epithelial cell (IEC) damage on T cell behavior. This has led to the identification of galactin-9 as playing an important role in driving CD4+ and CD8+ T cell responses. Congratulations to Suze Jansen and Alessandro Cutilli for all their work driving this study forward.

Highlights

Chemotherapy-induced intestinal epithelial damage can be modelled with organoids

3D-coculture model allows evaluation of epithelial damage on T cell homeostasis

Chemotherapy-induced epithelial damage modulates T cell activation and migration

Galectin-9 promotes T cell activation and migration in response to epithelial damage

Summary

The intestine is vulnerable to chemotherapy-induced damage due to the high rate of intestinal epithelial cell (IEC) proliferation. We have developed a human intestinal organoid-based 3D model system to study the direct effect of chemotherapy-induced IEC damage on T cell behavior. Exposure of intestinal organoids to busulfan, fludarabine, and clofarabine induced damage-related responses affecting both the capacity to regenerate and transcriptional reprogramming. In ex vivo co-culture assays, prior intestinal organoid damage resulted in increased T cell activation, proliferation, and migration. We identified galectin-9 (Gal-9) as a key molecule released by damaged organoids. The use of anti-Gal-9 blocking antibodies or CRISPR/Cas9-mediated Gal-9 knock-out prevented intestinal organoid damage-induced T cell proliferation, interferon-gamma release, and migration. Increased levels of Gal-9 were found early after HSCT chemotherapeutic conditioning in the plasma of patients who later developed acute GVHD. Taken together, chemotherapy-induced intestinal damage can influence T cell behavior in a Gal-9-dependent manner which may provide novel strategies for therapeutic intervention.

Chemotherapy-induced intestinal epithelial damage directly promotes galectin-9-driven modulation of T cell behavior. Suze A. Jansen# ,Alessandro Cutilli#, Coco de Koning, Marliek van Hoesel,Cynthia L. Frederiks, Leire Saiz Sierra,Stefan Nierkens, Michal Mokry, Edward E.S. Nieuwenhuis,Alan M. Hanash, Enric Mocholi, Paul J. Coffer* and Caroline A. Lindemans*

Welcome Claudia!

Cláudia Leite graduated in Biochemistry and holds a PhD in Molecular and Cell Biology from the University of Porto. During her PhD, she investigated how mitochondria adjusts their activity to regulate cell cycle progression in budding yeast. She has recently joined the Coffer lab as a postdoctoral researcher to investigate the role of nuclear acetyl-CoA-producing enzymes in regulating transcriptional reprograming.

Lab day out: canoeing in Holland's beautiful 'green heart'

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Paper: Nuclear metabolism controls chromatin remodelling during T cell activation

Extremely happy to have our study exploring nuclear metabolism in the control of chromatin remodeling published (link below). This became a huge project driven by Enric Mocholi and wouldn't have been possible without generous collaborations from groups in the EU, USA and Canada (through lockdown). A BIG thank you to all involved.

In brief

After T cell activation, histone acetylation and transcriptional reprogramming require glycolysis and the pyruvate dehydrogenase (PDH)-dependent production of extramitochondrial acetyl-CoA. Here we show that PDH translocates to the nucleus close to chromatin-remodeling complexes, highlighting how metabolic and histone-modifying enzymes cooperate in regulating T cell activation.

Highlights

- PDH is required for histone acetylation and transcription after T cell activation

- MPC1 and ACLY are not required for T cell activation and transcriptional reprogramming

- T cell activation leads to PDH nuclear translocation close to chromatin-remodeling complexes

Congratulations Dr. Anita Govers!

Many congratulations to Dr. Anita Govers who successfully defended her thesis "Epigenetic regulation of normal and aberrant myelopoiesis: a balancing act". It has been a long journey and super happy that we could celebrate this milestone together with co-promoter Dr. Marije Bartels. Many thanks to the thesis committee Prof. Marry van den Heuval-Eibrink, Prof. Femke van Wijk, Prof. Jurgen Kuball, Prof. Roland Kuiper, Prof. Joop Jansen en Dr. Marc Bierings.

In the last two decades, epigenetic changes have become more and more evident as a contributing factor in aberrant myelopoiesis, however the exact roles are yet poorly understood. Furthermore, knowledge about epigenetic regulation of normal hematopoiesis is far from complete. Nonetheless, the use of chromatin modifying drugs such as HDACi, has rapidly increased in the past years.

Work in this thesis is aimed to increase understanding the effects of epigenetic regulation and epigenetic modifiers on both normal and aberrant hematopoiesis.

Colorectal Cancer-Infiltrating Regulatory T Cells

Here, we review our understanding of the role of T regulatory (Treg) cells in colorectal cancer (CRC), the possible mechanisms that support their homeostasis in the tumour microenvironment, and current approaches for manipulating Treg cells function in cancer.

Colorectal cancer (CRC) is a heterogeneous disease with one of the highest rates of incidence and mortality among cancers worldwide. Understanding the CRC tumor microenvironment (TME) is essential to improve diagnosis and treatment. Within the CRC TME, tumor-infiltrating lymphocytes (TILs) consist of a heterogeneous mixture of adaptive immune cells composed of mainly anti-tumor effector T cells (CD4+ and CD8+ subpopulations), and suppressive regulatory CD4+ T (Treg) cells. The balance between these two populations is critical in anti-tumor immunity. In general, while tumor antigen-specific T cell responses are observed, tumor clearance frequently does not occur. Treg cells are considered to play an important role in tumor immune escape by hampering effective anti-tumor immune responses. Therefore, CRC-tumors with increased numbers of Treg cells have been associated with promoting tumor development, immunotherapy failure, and a poorer prognosis. Enrichment of Treg cells in CRC can have multiple causes including their differentiation, recruitment, and preferential transcriptional and metabolic adaptation to the TME. Targeting tumor-associated Treg cell may be an effective addition to current immunotherapy approaches. Strategies for depleting Treg cells, such as low dose cyclophosphamide treatment, or targeting one or more checkpoint receptors such as CTLA-4 with PD-1 with monoclonal antibodies, have been explored. These have resulted in activation of anti-tumor immune responses in CRC-patients. Overall, it seems likely that CRC-associated Treg cells play an important role in determining the success of such therapeutic approaches.

Full access to review paper here

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