PO-484 Immunohistochemical analysis of mTORC1 and mTORC2-related proteins in renal cell carcinoma of kidney transplant recipients

Abstract

IntroductionKidney transplantation improves survival and life quality for patients with end-stage renal disease (ESRD), however, immunosuppression leads to increased risk of cancer, including renal cell carcinoma (RCC). The PI3K/Akt/mTOR pathway has a fundamental role in renal physiology and its inhibitors are used as immunosuppressive as well as antitumour agents. Recent studies suggest that immunosuppressive regimen, especially calcineurin inhibitors, may affect mTOR pathway activation. The aim of our study was to analyse the expression of mTORC1 and mTORC2-related proteins in RCCs developed in kidneys of transplant recipients and healthy individuals as controls.Material and methodsExpression of p-mTOR (catalytic subunit of mTORC1 and mTORC2), p-S6 (mTORC1-related protein) and Rictor (mTORC2-related protein) was assessed in RCC tissues obtained from 46 kidney transplant recipients (15 clear cell RCCs, 31 papillary RCCs) and 46 healthy individuals (28 clear cell RCCs, 18 papillary RCCs) using IHC on tissue microarrays. Tissues from patients with ESRD (n=10) and normal kidney (n=3) were also studied.Results and discussionsIn normal kidney, expression of p-S6 and p-mTOR was weak in tubular epithelial cells. In contrast, expression of Rictor was high in the epithelium of both proximal and distal tubules. In ESRD, expression of p-mTOR, p-S6, and Rictor appeared to be higher in transplant recipients (n=6) compared to those who have not received immunosuppression (n=4). Expression of p-mTOR and Rictor was significantly higher in RCCs of diseased native kidneys of renal transplant recipients compared to RCCs developed in healthy individuals (p<0.01 and p<0.001, respectively) providing information about mTORC2 activation in post-transplant RCCs. According to previous observations, expression of p-S6 was significantly higher in clear cell RCCs as compared to papillary RCCs in both post-transplant and non-transplant patients (p<0.01 and p<0.05, respectively).ConclusionOur results highlighted the role of mTORC2 in the pathobiology of post-transplant RCCs. There are insufficient evidences for the protective role of mTORC1 inhibitors as immunosuppressive agents against post-transplant malignancies. Use of dual mTORC1/C2 inhibitors in the antitumour and immunosuppressive therapy needs further investigation and may represent a promising opportunity in the treatment or prevention of post-transplant RCCs.Supported by the ÚNKP-17–3, Bolyai Found of Hungarian Academy Sciences, and Semmelweis University Innovation Found STIA-KF-17.