Research Student #3

Nicola Mora

The role of STAT1 activation and immunity in ALCL oncogenesis

Medizinische Universität Wien

Supervisor: Olaf MERKEL


Research objectives:

The role of STAT1 has been understudied in ALCL because usually STAT1 is seen as an immunity-driven tumour suppressor.

In recent studies STAT1 has been shown to mediate the antitumor effect of aberrant ALK activity following intermittent ALK inhibitor dosing strategies, in keeping with another study arguing that STAT1 is deactivated by ALK. In contrast, we have recently shown that STAT1 mediates survival signals from the tyrosine kinase TYK2 to MCL1 suggesting an oncogenic role for this transcription factor. In FFPE tissue of primary patients we find high STAT1 and pYSTAT1 expression.

It is clear that the role of STAT1 requires further investigation. This will be achieved by:

  1. Knockout STAT1 in the well-established CD4/NPM-ALK mouse model of ALCL to study STAT1/STAT3 interactions and even more importantly the immunological effects of STAT1 knockout;
  2. To perform single cell RNAseq in wild-type and STAT1-/- murine tumours to assess anti-tumour immunity at a cellular level;
  3. Apply in vitro immune reporter systems to assess the effect of STAT1 knockout on the anti-tumour immune response;
  4. Investigate interactions of checkpoint proteins and their inhibitors that have recently been introduced into ALCL clinical trials, e.g., nivolumab with STAT1 will be assessed closely;

Clarify the role of STAT1 and the anti-tumour immune response in ALCL oncogenesis

Expected results:

Our data will provide insights into developing better strategies for ALCL immunotherapies as well as unique genetically engineered mouse models available to the consortium.

Planned secondments:

Year 1: Universitätsklinikum Freiburg: Analysis of immune cell profiles in the mouse model through learning the methodology that has been developed in the host lab (5 months)

Year 2: MLL Leukaemia lab: Conduct and analyse scRNAseq using equipment and expertise available at the MLL lab who will provide specific training (3 months)