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

Abstract

Immuno-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. 342 unselected consecutive RCC tumor samples were analyzed regarding their PD-1, PD-L1, and CTLA-4 expression by immunohistochemistry (IHC). The prognostic values for cancer-specific survival (CSS) and overall survival (OS) were analyzed for those not exposed to CI therapy. The expression of PD-1 in tumor-infiltrating mononuclear cells (TIMC) and PD-L1 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 TIMC (>1% positive cells) was detected in 4.8% and 6.3%. PD-1 expression and CTLA-4 expression were significantly associated with a worse OS and CSS in log rank survival analysis and univariate Cox regression analysis. CTLA-4 expression is a prognostic marker that is independently associated with a worse outcome in multivariate Cox 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 PD-1-expression are at highest risk in OS and CSS. In RCC patients, PD-1 expression in TIMC and CTLA-4 expression in TIMC are associated with a worse OS and CSS. The combination of PD-1 expression in TIMC and CTLA-4 expression in TIMC might identify high risk patients. This is, to our knowledge, the first description of CTLA-4 expression to be a prognostic marker in RCC.

Soluble forms of PD-L1 and PD-1 as prognostic and predictive markers of sunitinib efficacy in patients with metastatic clear cell renal cell carcinoma

“…6 PD-L1 expression by tumor cells is associated with worse prognosis for patients with many types of tumors including ccRCC. 7,8 Although PD-L1 staining appears to correlate with a better outcome from immune-based combinations like nivolumab-ipilimumab, 3 it is a poor discriminating factor for clinical decisions. Furthermore, the evaluation of PD-L1 expression by immunohistochemistry (IHC) has not been yet considered as a gold-standard.…”

Predictive Biomarkers of Response to Immunotherapy in Metastatic Renal Cell Cancer

“…In the setting of mRCC, the negative prognostic role of the expression of PD-L1 on tumor cells has been reported in several studies (25,26). Renal cancers showing the expression of PD-L1 on tumor cells display a higher tumor stage, a worse response to TKI therapy and a poorer prognosis (27). In details, in two post hoc analyses of the COMPARZ study and the METEOR and CABOSUN trials, respectively, PD-L1 expression on tumor cells was associated with shorter survival in mRCC patients, irrespectively of the type of targeted therapy received (28,29).…”

Metastatic Renal Cell Carcinoma Management: From Molecular Mechanism to Clinical Practice

“…Several studies have demonstrated the negative prognostic role of the expression of PD-L1 in the setting of mRCC (70)(71)(72). The expression of PD-L1 on tumor cells was associated with a higher tumor stage and a worse response to TKI therapy in two post-hoc analyses of the COMPARZ study and the METEOR and CABOSUN trials (28,(72)(73)(74). In addition, a meta-analysis including more than 1,300 patients showed that higher PD-L1 expression correlated with an approximately doubling risk of death (75).…”