Impaired thymic negative selection as a source of melanoma-reactive TCR specificities

Grantee: Kai Kisand, University of Tartu, Institute of Biomedicine and Translational Medicine

Amount: DKK 4,908,566

Grant category: Research Grants in open competition

Year: 2018

Geography: Estonia

Melanoma is a very aggressive type of cancer that affects people at their most productive period of the life. As most of the diagnosed patients should have a long life still ahead a cure of the disease is highly desired.

Cancer immunotherapy with checkpoint inhibitors and T cell adoptive therapy have established the crucial role of T cell responses in melanoma as well as in many other cancers. Successful immunotherapy of melanoma is often associated with vitiligo as a side effect indicating the importance of targeting the antigenic epitopes that are shared between melanocytes and melanoma cells.

However, melanocyte antigens are “self” and T cell receptor (TCR) specificities that recognise such epitopes with high affinity are deleted during their maturation in the thymus. To find high-affinity TCRs specific for melanocyte/melanoma antigens we will interrogate the TCR repertoire of a patient population that is defective in their central (thymic) tolerance induction mechanisms due to mutations in autoimmune regulator gene, and who develop vitiligo as one of their disease manifestations.

We expect to identify several TCR specificities that recognise melanocyte/melanoma antigenic epitopes. This information can be used for designing genetically modified T cells for adoptive treatment of melanoma patients, and to advance the knowledge about vitiligo pathogenesis and mechanisms of central tolerance induction.

The function and therapeutic potential of miR-146 family in the suppression of Type-2-cell-promoting environment in atopic dermatitis

Grantee: Ana Rebane, PhD, Head of the RNA Biology Research Group, Institute of Biomedicine and translational Medicine, University of Tartu

Amount: DKK 1,650,000

Grant category: Research Grants in open competition

Year: 2017

Geography: Estonia

Atopic dermatitis (AD) develops because of skin barrier abnormalities leading to activation of keratinocytes (KCs) and development of Type-2-cell- mediated chronic skin inflammation.

While the initial molecular events leading to induction of Type-2-cell-promoting cytokines are not well defined, it has been suggested that activation of the NF-kB pathway in response to environmental and/or intrinsic factors in KCs may be at play.

Concurrently, microRNAs – in particular miR-146a and miR-146b (miR-146a/b) – which are post-transcriptional gene expression regulators modulating various biological processes, have been shown to have an anti-inflammatory function in KCs and in the chronic phase of skin inflammation in AD.

In this project, Dr Rebane hypothesizes that miR-146a/b might inhibit AD-promoting events in the skin as these microRNAs act by targeting multiple factors in the NF-κB pathway.

Dr Rebane aims to study this relation using tissue culture and murine models, and assess the therapeutic potential in the regulation of Type-2-cell-promoting cytokines in the development of AD. In addition, it is planned to describe the expression of miR-146a/b isoforms and novel AD associated miRNAs in the skin of AD patients with the aim of detection of novel therapeutic targets.