Novel factors in the pathogenesis of cutaneous T cell lymphomas

This thesis concentrates on exploring novel agents in the pathogenesis of cutaneous T cell lymphomas (CTCL) and reveals potential new biomarkers and therapeutic targets to improve diagnostics. CTCLs are also known as a heterogeneous group of non-Hodgkin lymphomas. The clinical behavior of these lymphomas varies from benign forms of lymphoproliferative diseases such as lymphomatoid papulosis (LyP) to non-progressive mycosis fungoides (MF) and further to rapidly-progressing leukaemic Sézary syndrome (SS). The incidence of the disease is growing, particularly in Western countries. The mechanisms underlying the disease are still largely unknown and thus far no curative therapy exists. Regarding pathogenesis, it has been suggested that persistent antigen stimulation leads to continuous stimulation of T cells and chronic inflammation, eventually causing the development of a malignant T cell clone. Another hypothesis suggests that a specific viral agent could serve as a triggering factor. The first part of this thesis explores the activity of human endogenous retroviruses (HERVs) in CTCLs. HERVs are retroviral sequences comprising about 8% of the human genome and are derived from ancient retrovirus infections of germ line cells. HERVs have their own promoter areas and genes, some of which encode functional proteins. HERVs may also affect the function of neighbouring genes and influence chromosomal instability (e.g. due to random positioning in the genome). However, HERVs are usually epigenetically silenced, but are reactivated in situtations such as cancer. Healthy tissues also show HERV activity. Moreover, tissue-specificity is typical feature of HERVs. We show that a skin-specific HERV pattern is actively transcribed in MF. We also found that the HERV-W-derived viral protein Syncytin-1 is expressed in morphologically malignant lymphocytes. The second part of this thesis is a unique molecular study on a rare subtype of CTCL. Known as subcutaneous panniculitis-like T cell lymphoma (SPTL), this subtype primarily affects young individuals. The diagnosis of SPTL is challenging and SPTL is usually confused with other panniculitis-related inflammatory diseases. The most important finding of the gene expression profiling was the high expression of indoleamine-2,3-dioxygenase (IDO-1), which catabolises the essential amino acid tryptophan (Trp) into kynurenine (Kyn) metabolites. The enzymatic activity of IDO-1 results in the depletion of Trp in the local microenvironment. Because T cells are particularly sensitive to low Trp levels, the process ultimately leads to immunosuppression and subsequent inhibition of T cell responses. Our results suggest that autoimmune inflammation is underlying the development the disease with the support of an immunosuppressive microenvironment. The last part of this thesis is focused on further studying IDO-1 expression in other CTCL subtypes and lymphoproliferative diseases and also how the tumor microenvironment could be involved in malignant transformation. In this study, we showed that distinct subpopulations of CTCL can be recognized based on IDO1-expressing cells. Especially interesting was the finding that IDO-1 is more extensively expressed in LyP rather than in MF, bearing in mind that LyP is a benign disease. Analyzing the Kyn/Trp ratio from patient sera also showed significant differences between MF and LyP. The Kyn/Trp ratio may therefore serve as a potential prognostic biomarker for evaluating disease activity. Taken together, this study revealed completely new information on gene and protein expression in CTCL. The results will likely be most useful in improving future diagnostics as well as patient care. The results may also be further applied in finding new therapeutic targets and developing novel therapies.