Expression of PD-1 and CTLA-4 Are Negative Prognostic Markers in Renal Cell Carcinoma

Abstract

Background: Immun-oncological therapy with checkpoint inhibition (CI) has become a new standard treatment in metastatic renal cell carcinoma (RCC) but the prognostic value of the expression of CI therapy target molecules is still controversial. Material and Methods: 342 unselected consecutive RCC tumor samples were analyzed regarding their PD-1, PD-L1 and CTLA-4 expression by immunohistochemistry (IHC). The prognostic value for cancer-specific (CSS) and overall survival (OS) was analyzed. Results: Expression of PD-1 in tumor-infiltrating mononuclear cells (TIMC) and PDL1 in tumor cells was detected in 9·4% and 12·3% respectively (Immune reactive score (IRS) >0). Furthermore, PD-L1 expression in TIMC (IRS>0) and CTLA-4 expression in tumor tissue (>1% positive cells) was detected in 4·8% and 6·3%. PD-1 expression and CTLA-4 expression were significantly associated with worse OS and CSS in log rank survival analysis and univariate Cox's regression analysis. CTLA-4 expression is a prognostic marker, independently associated with worse outcome in multivariate Cox's regression analysis in the whole cohort (OS: p=0·013; CSS: p=0·048) as well as in a non-metastatic subgroup analysis (OS: p=0·028; CSS: p=0·022). Patients with combined CTLA-4 expression and PD1-expression are at highest risk in OS and CSS. Conclusion: In RCC patients, PD-1 expression in TIMC and CTLA-4 expression in cells in tumor tissue are associated with worse OS and CSS. The combination of PD-1 expression in TIMC and CTLA-4 expression in cells in tumor tissue might identify high risk patients. This is to our knowledge the first description of CTLA-4 expression to be a prognostic marker in RCC. Funding Statement: All investigations were financed from clinical funds of the participating institutes. All funding sources had no involvement in data collection, analysis, interpretation, writing, and the decision to submit the paper for publication. Declaration of Interests: AK reports personal fees and non-financial support from Bayer, personal fees and non-financial support from Pfizer, non-financial support from Novartis, non-financial support from Sanofi Avensis, non-financial support from BMS, and non-financial support from Ipsen; all outside the submitted work. AH reports grants, personal fees and non-financial support from Roche, personal fees from Astra Zeneca, personal fees and non-financial support from BMS, personal fees and non-financial support from MSD, grants and personal fees from Cepheid, grants and personal fees from Biontech, grants and personal fees from Qiagen, personal fees from Abbvie, grants and personal fees from Novartis, personal fees from Boehringer Ingelheim, and grants and personal fees from Janssen; all outside the submitted work. PJG reports personal fees and non-financial support from BMS, personal fees and non-financial support from Roche, personal fees and non-financial support from Novartis, personal fees and non-financial support from Bayer, personal fees and non-financial support from AstraZeneka, personal fees and non-financial support from Janssen, personal fees and non-financial support from Ipsen, and personal fees and non-financial support from Eisal; all outside the submitted work. BW reports personal fees from Astellas and personal fees from Jansssen-Cilag; all outside the submitted work. CGS, SW, HT, and FE have nothing to disclose. Ethics Approval Statement: The study was carried out according to the latest version of the Declaration of Helsinki and is approved by the institutional ethics committee.