High IDO-1 Expression in Tumor Endothelial Cells is Associated with Response to Immunotherapy in Metastatic Renal Cell Carcinoma

Summary

Nivolumab belongs to the standard therapy in the second-line setting of metastatic renal cell carcinoma (mRCC). Although deep and long-lasting responses are seen in some patients, the majority of patients will further progress. PD-L1 as predictive biomarker is still under critical evaluation. Thus, more accurate biomarkers are clearly warranted. Here, we investigated for the first time the predictive role of IDO-1, a negative immune-regulatory molecule, on clear cell RCC tissues of 15 patients undergoing nivolumab therapy. IDO-1 and other immune inhibitory molecules (PD-L1, PD-L2, FOXP3) as well as immune cell subsets (CD3, CD4, CD8) were measured on formalin-fixed, paraffin-embedded sections of RCC specimens by immunohistochemistry. IDO-1 was predominantly expressed in tumor endothelial cells, and was totally absent from tumor cells itself. IDO-1 overexpression (>10%) could be detected more frequently in responders (100%, n=6/6) compared to non-responders (33.3%, n=3/9; p=0.028), resulting in a better progression-free survival during immunotherapy (IDO-1 ≤10% vs. >10%, median: 3.5 vs. NE months, p=0.01 by log-rank test). In addition, IDO-1 was positively correlated with CD8⁺ T cell expression (r_s=0.691, p=0.006). PD-L1 expression on tumor cells was negative in 13 (86.7%) of 15 patients, irrespective of therapeutic response (responders vs. non-responders: 83.3% vs. 88.9%). No differences were noticed in the PD-L1 expression on tumor-infiltrating immune cells (PD-L1<1% in 66.7% of both responders and non-responders). In contrast to PD-L1, these results suggest that IDO-1 may be a more promising predictive biomarker for response to immune-based cancer therapy in mRCC.

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