Research Student #1

Carla Vasquez-Amos

Investigating the role of the T cell receptor (TCR) in ALCL pathogenesis towards the development of an innovative therapeutic approach

Masarykova Univerzita - Medical Faculty - CEITEC

Supervisor: Suzanne TURNER


Research objectives:

A defining feature of ALCL is the lack of expression of a TCR despite the cells of origin being T cells. The enigma as to why the TCR is not expressed has been studied in the host lab whereby the capacity to express a TCR is still an option for some ALCL, being internalised rather than absent, through a lack of transcription or genetic deletion of TCR-encoding genes. This data suggests that the TCR is actively internalised perhaps due to a tumour-derogatory role if it is expressed on the surface.

Indeed, our data shows that co-expression of a TCR and aberrant expression of ALK in primary T cells results in a signalling overload and cell death, particularly when the expressed TCR is engaged by cognate ligand. These findings will be investigated further as they might apply to:

  1. The origins of this largely paediatric malignancy and;
  2. The therapy of this cancer.

Employing a genetically engineered mouse model in which NPM-ALK is expressed in T cells through the CD4 promoter (CD4/NPM-ALK) together with forced expression of a TCR that specifically recognises ovalbumin antigen (OVA – OTI transgenic), mice will be exposed to murine herpes virus carrying OVA peptides of varying avidity for the TCR. The effects this has on tumour development in vivo will be monitored by MRI and ex vivo tumour phenotyping for tumour cell ontogeny and immune cell infiltration with a particular focus on comparing the ensuing tumours, should they develop, with the human malignancy.

In the second aim, these data will be interpreted towards a therapeutic outcome, e.g., if an antigen with high avidity drives apoptosis and prevents tumour growth, this might imply that established tumours (lacking a TCR) could be targeted therapeutically by forcing enhanced signalling through distal TCR signalling pathways rather than their inhibition. Towards this aim, patient derived xenografts (PDX) of ALCL developed in the lab of B#1 and 3 will be analysed for their response to select phosphatase inhibitors (in contrast to traditionally applied kinase inhibitors).

Expected results:

We predict that engaging the TCR with a high avidity peptide will prevent tumour growth in CD4/NPM-ALK/OTI transgenic mice whereas weakly binding peptides will be tolerated with tumour growth ensuing. This would suggest that an autoantigen or tonic stimulation of T cells might play a role in ALCL development. Alternatively, that high avidity stimulation results in TCR down-regulation as both the stimulated TCR and oncogenic ALK expression are ‘overload’ for the incipient tumour cells. In turn, this will allow us to speculate on therapeutic targets that, contrary to accepted dogma which tells us to inhibit proliferation-promoting signalling in tumour cells, might instead be over-stimulated by, for example, inhibiting phosphatase activity.

Planned secondments:

Year 2: CBMed: Analysis of murine tumour tissue sections applying technologies available at CBMed (3 months)

Year 3: University of Torino: Access to PDX models of ALCL that are uniquely available at the host institute (3 months)