The utilisation of biomarkers of a reduced immune response to predict squamous cell carcinoma in long-term renal transplant recipients

Cutaneous squamous cell carcinoma (SCC) is the most common malignancy in renal transplant recipients (RTR) with an incidence up to 250 times that of the general population. SCC is frequently recurrent and more aggressive than in non-transplant cohorts. Immunological and clinical measures have been developed to stratify RTR by future SCC risk but their comparative performance in long-term RTR has not been assessed. We hypothesised that biomarkers of two potential mechanisms underlying a reduced immune response may predict SCC development. These biomarkers comprised ‘signatures’ of immune regulation developed in RTR who have successfully ceased immunosuppression without development of graft dysfunction ('operational tolerance') and immunophenotypic changes associated with immunosenescence. Immunosenescence leads to a reduction of immune responses with increasing age. A prospective cohort study was undertaken of 117 long-term RTR, half with a history of previous SCC. RTR were stratified by phenotype based on a majority ('CD57hi') or minority ('CD57lo') of peripheral blood CD8+ T cells expressing CD57. CD57hi RTR were 2.4 times more likely to develop SCC during follow-up, independent of age or history of previous SCC. This was more predictive than previously developed clinical and immunological measures. CD57hi RTR exhibited other functional and phenotypic changes associated with immunosenescence. Signatures of operational tolerance did not predict SCC risk but were heavily influenced by the effect upon circulating B cells due to immunosuppressive regime, particularly azathioprine and calcineurin inhibition. Further evaluation indicated that azathioprine use was associated with the presence of donor-specific antibodies. This study indicates that biomarkers of 'operational tolerance' are confounded by immunosuppression use and may not be suitable for clinical application in their current format. Biomarkers of immunosenescence, such as the CD57hi phenotype proposed in this study, may identify RTR at increased risk of subsequent SCC who may benefit from pre-emptive immunosuppression reduction.