Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Vieyra Garcia, P.
Pathophysiology of cutaneous T-cell lymphoma: Understanding of neoplastic T- cells and non-malignant infiltrate in lesional skin
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp.
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- Autor*innen der Med Uni Graz:
- Wolf Peter
- Betreuer*innen:
- Cerroni Lorenzo
- Heinemann Akos
- Wolf Peter
- Altmetrics:
- Abstract:
- In Mycosis fungoides (MF), neoplastic T-cells feed from chronic inflammation, their survival and resilience to therapy is closely tied to an abnormal pro- inflammatory microenvironment. Malignant cells produce recruitment mediators and growth factors and as disease progress, these cells accumulate mutations that enable them to better suit their environment. As skin lesions deteriorate, patients are left unable to fence off opportunistic pathogens and recurrent infections may end up with fatal consequences. Neoplastic cells are just a fraction of the infiltrating cells found in lesional MF skin. Although these cells in most cases outnumber with their predominant clonality the rest of the T-cell population, benign T-cells and other immune cell types nevertheless play an important role in the disease. This is evidenced by the fact that therapeutic strategies that induce immune tolerance and apoptosis like psoralen + UVA (PUVA) and extracorporeal photopheresis have a high degree of efficiency; nonetheless, the mechanistic effect of immune modulation has remained elusive. In this work, the effects of PUVA on neoplastic cells, benign T-cells, and other immune cells that infiltrate skin lesions of MF patients were investigated. Transcriptional analyses of lesional skin showed enriched expression of T-cell activation-related, antigen processing-presentation and JAK-STAT signalling genes. After PUVA therapy, the expression of many of these genes was partially normalized. Lesional skin had a high number of neoplastic and benign T-cells producing IL-9. In vitro studies indicated that the production of this cytokine was regulated by STAT3/5 and IRF4. High throughput sequencing (HTS) of the T- cell receptor (TCR) was used to look at the T-cell repertoire and identified malignant clones in skin biopsies from patients. Although patients had a significant clinical improvement to PUVA, remaining malignant clones were found in biopsies after treatment and clinical response correlated with benign T-cell turnover. Multicolour immunofluorescence was used to look at the composition of the cell infiltrate in lesional skin and a decrease of Langerhans cells and skin resident T-cells was observed after PUVA. These results emphasize the importance of inflammatory mediators like IL-9 and its regulators as well as the non-malignant immune cell infiltrate in the pathophysiology of MF. The mouse in vivo studies of this work in which the administration of an IL-9 blocking antibody delayed tumour growth and prolonged survival of animals, suggested that such anti-inflammatory treatment strategy could be beneficial to MF patients. Further efforts are needed to explore the targeting of neoplastic cells like the ones here presented with IL-9 as one of the key molecules in the onset of MF.