Prognostic significance and immune correlates of CD73 expression in renal cell carcinoma
Background CD73–adenosine signaling in the tumor microenvironment is immunosuppressive and may be associated with aggressive renal cell carcinoma (RCC). We investigated the prognostic significance of CD73 protein expression in RCC leveraging nephrectomy samples. We also performed a complementary ana...
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e001467.full |
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| author | Neeraj Agarwal Sabina Signoretti David F McDermott Toni K Choueiri Wanling Xie John A Steinharter Nieves Martinez-Chanza Bradley A McGregor Lauren C Harshman Abhishek Tripathi Xiao X Wei Edwin Lin Abdallah Flaifel Emily N Stern Gatof Gabrielle Bouchard Justin H Fleischer Connor Gray Charlene Mantia Linda Thompson Marios Giannakis |
| author_facet | Neeraj Agarwal Sabina Signoretti David F McDermott Toni K Choueiri Wanling Xie John A Steinharter Nieves Martinez-Chanza Bradley A McGregor Lauren C Harshman Abhishek Tripathi Xiao X Wei Edwin Lin Abdallah Flaifel Emily N Stern Gatof Gabrielle Bouchard Justin H Fleischer Connor Gray Charlene Mantia Linda Thompson Marios Giannakis |
| author_sort | Neeraj Agarwal |
| collection | DOAJ |
| description | Background CD73–adenosine signaling in the tumor microenvironment is immunosuppressive and may be associated with aggressive renal cell carcinoma (RCC). We investigated the prognostic significance of CD73 protein expression in RCC leveraging nephrectomy samples. We also performed a complementary analysis using The Cancer Genome Atlas (TCGA) dataset to evaluate the correlation of CD73 (ecto-5′-nucleotidase (NT5E), CD39 (ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1)) and A2 adenosine receptor (A2AR; ADORA2A) transcript levels with markers of angiogenesis and antitumor immune response.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. |
| format | Article |
| id | doaj-art-fdf81e1da90d4c78b0738c85b10bd5c7 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-fdf81e1da90d4c78b0738c85b10bd5c72024-11-10T01:40:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-001467Prognostic significance and immune correlates of CD73 expression in renal cell carcinomaNeeraj Agarwal0Sabina Signoretti1David F McDermott2Toni K Choueiri3Wanling Xie4John A Steinharter5Nieves Martinez-Chanza6Bradley A McGregor7Lauren C Harshman8Abhishek Tripathi9Xiao X Wei10Edwin Lin11Abdallah Flaifel12Emily N Stern Gatof13Gabrielle Bouchard14Justin H Fleischer15Connor Gray16Charlene Mantia17Linda Thompson18Marios Giannakis195University of Utah, Salt Lake City, UT, USA13Brigham and Women’s Hospital, Boston, MA, USADepartment of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA1 Harvard Medical School, Boston, Massachussetts, USA3 Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA1 Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA2 Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USAThe Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA1 Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA5 Hematology Oncology, University of Oklahoma Stephenson Cancer Center, Oklahoma City, Oklahoma, USA1 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA3 University of Utah, Huntsman Cancer Institute, Salt Lake City, Utah, USA5 Brigham and Women`s Hospital, Boston, Massachusetts, USA6 Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA2 Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA2 Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA6 Beth Israel Deaconess Medical Center, Boston, Massachusetts, USADana-Farber Cancer Institute, Boston, Massachusetts, USA1Lewis-Manning Hospice Care, Poole, UKDepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USABackground CD73–adenosine signaling in the tumor microenvironment is immunosuppressive and may be associated with aggressive renal cell carcinoma (RCC). We investigated the prognostic significance of CD73 protein expression in RCC leveraging nephrectomy samples. We also performed a complementary analysis using The Cancer Genome Atlas (TCGA) dataset to evaluate the correlation of CD73 (ecto-5′-nucleotidase (NT5E), CD39 (ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1)) and A2 adenosine receptor (A2AR; ADORA2A) transcript levels with markers of angiogenesis and antitumor immune response.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.https://jitc.bmj.com/content/8/2/e001467.full |
| spellingShingle | Neeraj Agarwal Sabina Signoretti David F McDermott Toni K Choueiri Wanling Xie John A Steinharter Nieves Martinez-Chanza Bradley A McGregor Lauren C Harshman Abhishek Tripathi Xiao X Wei Edwin Lin Abdallah Flaifel Emily N Stern Gatof Gabrielle Bouchard Justin H Fleischer Connor Gray Charlene Mantia Linda Thompson Marios Giannakis Prognostic significance and immune correlates of CD73 expression in renal cell carcinoma Journal for ImmunoTherapy of Cancer |
| title | Prognostic significance and immune correlates of CD73 expression in renal cell carcinoma |
| title_full | Prognostic significance and immune correlates of CD73 expression in renal cell carcinoma |
| title_fullStr | Prognostic significance and immune correlates of CD73 expression in renal cell carcinoma |
| title_full_unstemmed | Prognostic significance and immune correlates of CD73 expression in renal cell carcinoma |
| title_short | Prognostic significance and immune correlates of CD73 expression in renal cell carcinoma |
| title_sort | prognostic significance and immune correlates of cd73 expression in renal cell carcinoma |
| url | https://jitc.bmj.com/content/8/2/e001467.full |
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