Prognostic significance and immune correlates of CD73 expression in renal cell carcinoma.
Abstract | BACKGROUND: METHODS: Patients with RCC with available archived nephrectomy samples were eligible for inclusion. Tumor CD73 protein expression was assessed by immunohistochemistry and quantified using a combined score (CS: % positive cells×intensity). Samples were categorized as CD73negative (CS=0), CD73low or CD73high (< and ≥median CS, respectively). Multivariable Cox regression analysis compared disease-free survival (DFS) and overall survival (OS) between CD73 expression groups. In the TCGA dataset, samples were categorized as low, intermediate and high NT5E, ENTPD1 and ADORA2A gene expression groups. Gene expression signatures for infiltrating immune cells, angiogenesis, myeloid inflammation, and effector T-cell response were compared between NT5E, ENTPD1 and ADORA2A expression groups. RESULTS: Among the 138 patients eligible for inclusion, 'any' CD73 expression was observed in 30% of primary tumor samples. High CD73 expression was more frequent in patients with M1 RCC (29% vs 12% M0), grade 4 tumors (27% vs 13% grade 3 vs 15% grades 1 and 2), advanced T-stage (≥T3: 22% vs T2: 19% vs T1: 12%) and tumors with sarcomatoid histology (50% vs 12%). In the M0 cohort (n=107), patients with CD73high tumor expression had significantly worse 5-year DFS (42%) and 10-year OS (22%) compared with those in the CD73negative group (DFS: 75%, adjusted HR: 2.7, 95% CI 1.3 to 5.9, p=0.01; OS: 64%, adjusted HR: 2.6, 95% CI 1.2 to 5.8, p=0.02) independent of tumor stage and grade. In the TCGA analysis, high NT5E expression was associated with significantly worse 5-year OS (p=0.008). NT5E and ENTPD1 expression correlated with higher regulatory T cell (Treg) signature, while ADORA2A expression was associated with increased Treg and angiogenesis signatures. CONCLUSIONS: High CD73 expression portends significantly worse survival outcomes independent of stage and grade. Our findings provide compelling support for targeting the immunosuppressive and proangiogenic CD73-adenosine pathway in RCC.
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Authors | Abhishek Tripathi, Edwin Lin, Wanling Xie, Abdallah Flaifel, John A Steinharter, Emily N Stern Gatof, Gabrielle Bouchard, Justin H Fleischer, Nieves Martinez-Chanza, Connor Gray, Charlene Mantia, Linda Thompson, Xiao X Wei, Marios Giannakis, Bradley A McGregor, Toni K Choueiri, Neeraj Agarwal, David F McDermott, Sabina Signoretti, Lauren C Harshman |
Journal | Journal for immunotherapy of cancer
(J Immunother Cancer)
Vol. 8
Issue 2
(11 2020)
ISSN: 2051-1426 [Electronic] England |
PMID | 33177176
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ. |
Chemical References |
- GPI-Linked Proteins
- 5'-Nucleotidase
- NT5E protein, human
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Topics |
- 5'-Nucleotidase
(immunology)
- Carcinoma, Renal Cell
(genetics, immunology, pathology, therapy)
- Female
- GPI-Linked Proteins
(immunology)
- Gene Expression Profiling
- Humans
- Immunotherapy
- Kidney Neoplasms
(genetics, immunology, pathology, therapy)
- Male
- Prognosis
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