High IDO‐1 expression in tumor endothelial cells is associated with response to immunotherapy in metastatic renal cell carcinoma

Abstract

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 is still under critical evaluation as a predictive biomarker. 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 and 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 = .028), resulting in a better progression‐free survival during immunotherapy (IDO‐1 ≤ 10% vs >10%, median: 3.5 vs not estimated (NE) months, P = .01 by log‐rank test). In addition, IDO‐1 was positively correlated with CD8+ T cell expression (r s = .691, P = .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.

Peritumoral endothelial indoleamine 2, 3-dioxygenase expression is an early independent marker of disease relapse in colorectal cancer and is influenced by DNA mismatch repair profile

“…From a clinical perspective, it is essential to better identify individual patients that will benefit from immunotherapy, in order to reach the best treatment efficacy in individual patients taking into account that these treatments are associated with significant costs and potential toxicities. A recent study in a small group of patients with metastatic renal cell carcinoma demonstrated that endothelial IDO expression was more frequently present in the group of responders to anti-PD1 therapy versus non-responders (100% versus 33.3%) [ 27 ]. Our data suggest that IDO-inhibitory strategies might be beneficial in both MSI-H and MSS tumors.…”

Immunotherapy in Renal Cell Carcinoma: The Future Is Now

“…A comprehensive immune phenotype including other immunosuppressive factors such as TGFβ or IDO-1 and a better characterization of immune cells could be another step forward in the search of predictive biomarkers. Interestingly, IDO-1 expression was higher in endothelial cells of responders to nivolumab in a cohort of 15 patients with metastatic RCC [73]. This results in a reduced influx of tryptophan in the surrounding tumour tissue leading to a decrease in tumour proliferation.…”

The Tumor Vascular Endothelium as Decision Maker in Cancer Therapy

“…Increased IDO-1 expression levels were already associated with tumor progression, poor prognosis, and a decreased overall survival ( 82 , 83 ). IDO-1 expression can be found in different tumor cells, normal epithelial cells, monocyte-derived cells and in particular also in tumor endothelial cells ( 84 – 86 ). Of note, in some tumor entities, the tumor endothelial cells rather than tumor cells were shown to be responsible for increased IDO expression, e.g., in metastatic renal cell carcinoma ( 84 ).…”

“…Of note, in some tumor entities, the tumor endothelial cells rather than tumor cells were shown to be responsible for increased IDO expression, e.g., in metastatic renal cell carcinoma ( 84 ). IDO-1 expression levels in tumor endothelial cells were further suggested being a predictive biomarker for the response to immune-based cancer therapy ( 86 – 88 ). For example, in colorectal cancer, IDO-1 expression by host endothelial cells was a negative prognostic factor for regression free survival, independent of disease stage ( 89 ).…”