PD1, PD-l1 and CTLA4 expression in advanced renal cell carcinoma types

PD1, PD-L1 AND CTLA4 Expression In Advanced Renal Cell Carcinoma Types Introduction: Renal cell carcinoma (RCC) is a type of cancer which frequency is increasing all over the world and has poor response to treatment, especially in advanced stage cases. It is known that RCC is one of the tumors with a rich microenvironment. Current studies focus on immune checkpoints, and checkpoint inhibition (CI) treatments that prevent the tumor from escaping from the immune response are being tested on these patients. It is still unclear which patient will benefit more from the treatment. The aim of our study is to distinguish between PD-L1 in tumor cells and PD-1, PD-L1 and CTLA-4 expression in tumor infiltrating mononuclear cells (TIMC) between the 3 most common RCC types, clear cell, papillary and chromophobe RCCs to differentiate between low and advanced stages and to reveal their effects on prognosis and survival. Materials and Methods: In this study, one hundred and sixty six RCC cases diagnosed between 2010-2019 in Cukurova University Faculty of Medicine, Department of Pathology were included. PD-1, PD-L1, CTLA-4 markers were applied to the paraffin blocks of the cases using immunohistochemical method and their expression status was evaluated by distinguishing subtypes in advanced and low stage RCCs. Results: In our study, it was observed that PD-L1 positivity in the tumor in clear cell RCC was statistically significantly more frequent in advanced stage cases compared to lower stage (p: 0.006). On the other hand, in TIMC, no significant difference was found between the advanced and low stage expressions of PD-L1, PD1, CTLA-4. It was concluded that cases with PD-L1 positivity in TIMC in clear cell and chromophobe RCC had a shorter survival (p: 0.009 and p <0.001). The frequency of perinephritic fat invasion and necrosis was higher in cases with PD-L1 expression in TIMC was found. It was determined that PD-L1 in tumor and PD-1 and CTLA-4 expressions in TIMC had no effect on survival clear cell, papillary and chromophobe RCC. Unlike other types, it has been observed that CTLA-4 expression is higher in papillary RCC. Conclusions: In this study, it was observed that PD-L1 was expressed more frequently in tumor cells in advanced stage clear cell RCC compared to lower stage, and PD-L1 expression in TIMC significantly shortened survival in clear cell and chromophobe renal cell carcinomas. In addition, it was found that the frequency of perinephritic fat invasion, necrosis and metastasis increased in RCCs with PD-L1 expression. It has been shown that PD-1 and CTLA-4 expressions do not affect the prognosis in RCC. We think that PD-L1, PD-1 and CTLA-4 must be considered together in advanced stage RCC for the treatment of both two pathway inhibitors and beyond this it can be more fair to use inhibitors of CTLA-4 pathway in papillary RCC. Further large studies will shed light on the immunotherapy options at the advanced stage of all RCC types even in the absence of metastasis. Key words: Renal cell carcinoma, PD-1, PD-L1, CTLA-4