B124
Analysis of STAT3 activation and the immunological microenvironment of paediatric solid tumours by tissue array immunohistochemistry
Fyeza Hasan1, Daniel Morgenstern1, Piku Basu2, Neil Sebire1, Sian Gibson1, John Anderson1
1University College London, Institute of Child Health and Great Ormond Street Hospital, UK, 2University of London School of Pharmacy, UK
STAT3 is a pivotal oncogenic transcription factor that effects two equally important mechanisms of tumour growth inhibition, firstly an intrinsic pleiotropic growth promoting function, and secondly cross-talk to induce STAT3 activation within haemopoietic and stromal cells of the tumour microenvironment that cloak the tumour from immune detection. We recently identified STAT3 to be specifically activated in alveolar rhabdomosarcoma (Nabarro et al J Exp Med 202(10) 1399-1410) so hypothesised that STAT3 activation in other paediatric tumour types would be asssociated with evidence of immune evasion.
To investigate the incidence of STAT3 activation and its relation to the immune environment we generated tissue arrays corresponding to 8 paediatric tumour histologies. STAT3 activation was determined by staining with a phospho-specific antibody, and the immunological environment was assessed by staining with antibodies specific for CD3, FOXP3, CD68 and IDO.
The paediatric tumours studied (Ewings, wilms, mesoblastic nephroma, rhabdoid, osteosarcoma, neuroblastoma, undifferentiated sarcoma, ependymoma, medulloblastoma) were all characterised by a paucity of infiltrating CD3 positive cells (T cells or NKT cells) and there was no evidence for a preponderance of FOXP3 positive regulatory T cells. In all tumours there was evidence for a population of STAT3 activated cells in conjunction with blood vessels. Similarly a dense population of CD68 positive myeloid cells was strongly localised with non-necrotic areas in the region of the STAT3 activated cells around vessels. High levels of STAT3 activation in tumour cells was seen in Ewing family tumours and ependymoma but not in the other histologies.
Like alveolar rhabdomyosarcoma, other paediatric tumours show very little lymphocytic infitrate but unlike ARMS, the mechanism in most tumours appear to be STAT3 independent. Whilst cominbing immunotherapy with STAT3 inhibtion appears an attractive proposition in Ewing family tumours, for other histologies it will be important to identify the mechanisms of immune evasion. Characterisation of the STAT3 activated cells and myeloid cells around vessels is our current focus.
