Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis
Background Non-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that biomarkers of immune dysregul...
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BMJ Publishing Group
2023-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/1/e006222.full |
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| author | Sandra M Herrmann Riley Fadden Ryan J Sullivan Kerry L Reynolds Harish Seethapathy Meghan E Sise Shruti Gupta Alexandra-Chloe Villani Qiyu Wang Daiana Moreno Destiny Harden R Neal Smith Ivy A Rosales Robert B Colvin Sarah Chute Lynn D Cornell Nancy J Yang Sara Barmettler Sophia Wells Jocelyn Farmer |
| author_facet | Sandra M Herrmann Riley Fadden Ryan J Sullivan Kerry L Reynolds Harish Seethapathy Meghan E Sise Shruti Gupta Alexandra-Chloe Villani Qiyu Wang Daiana Moreno Destiny Harden R Neal Smith Ivy A Rosales Robert B Colvin Sarah Chute Lynn D Cornell Nancy J Yang Sara Barmettler Sophia Wells Jocelyn Farmer |
| author_sort | Sandra M Herrmann |
| collection | DOAJ |
| description | Background Non-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that biomarkers of immune dysregulationpreviously defined in patients with congenital CTLA4 deficiency, including elevated soluble interleukin-2 receptor alpha (sIL-2R) and flow cytometric cell-based markers of B and T cell dysregulation in peripheral blood may aid the diagnosis of ICI-nephritis.Methods A retrospective cohort of patients diagnosed with ICI-nephritis was compared with three prospectively enrolled control cohorts: ICI-treated controls without immune-related adverse events, patients not on ICIs with hemodynamic acute kidney injury (hemodynamic AKI), and patients not on ICIs with biopsy proven acute interstitial nephritis from other causes (non-ICI-nephritis). sIL-2R level and flow cytometric parameters were compared between groups using Wilcoxon rank sum test or Kruskal-Wallis test. Receiver operating characteristic curves were generated to define the accuracy of sIL-2R and flow cytometric biomarkers in diagnosing ICI-nephritis. The downstream impact of T cell activation in the affected kidney was investigated using archived biopsy samples to evaluate the gene expression of IL2RA, IL-2 signaling, and T cell receptor signaling in patients with ICI-nephritis compared with other causes of drug-induced nephritis, acute tubular injury, and histologically normal controls.Results sIL-2R level in peripheral blood was significantly higher in patients with ICI-nephritis (N=24) (median 2.5-fold upper limit of normal (ULN), IQR 1.9–3.3), compared with ICI-treated controls (N=10) (median 0.8-fold ULN, IQR 0.5–0.9, p<0.001) and hemodynamic AKI controls (N=6) (median 0.9-fold-ULN, IQR 0.7–1.1, p=0.008). A sIL-2R cut-off point of 1.75-fold ULN was highly diagnostic of ICI-nephritis (area under the curve >96%) when compared with either ICI-treated or hemodynamic AKI controls. By peripheral blood flow cytometry analysis, lower absolute CD8+T cells, CD45RA+CD8+ T cells, memory CD27+B cells, and expansion of plasmablasts were prominent features of ICI-nephritis compared with ICI-treated controls. Gene expressions for IL2RA, IL-2 signaling, and T cell receptor signaling in the kidney tissue with ICI-nephritis were significantly higher compared with controls.Conclusion Elevated sIL-2R level and flow cytometric markers of both B and T cell dysregulation may aid the diagnosis of ICI-nephritis. |
| format | Article |
| id | doaj-art-b2896a0a2c844123a9938a6aff85c060 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-b2896a0a2c844123a9938a6aff85c0602025-01-29T09:05:14ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-01-0111110.1136/jitc-2022-006222Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritisSandra M Herrmann0Riley Fadden1Ryan J Sullivan2Kerry L Reynolds3Harish Seethapathy4Meghan E Sise5Shruti Gupta6Alexandra-Chloe Villani7Qiyu Wang8Daiana Moreno9Destiny Harden10R Neal Smith11Ivy A Rosales12Robert B Colvin13Sarah Chute14Lynn D Cornell15Nancy J Yang16Sara Barmettler17Sophia Wells18Jocelyn Farmer19Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA2 Mass General Cancer Center, Boston, MA, USA2Harvard Medical School, Massachusetts General Hospital, Needham, MA, USA3 Harvard Medical School, Boston, Massachusetts, USADivision of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USADepartment of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USABrigham and Women`s Hospital, Boston, Massachusetts, USADepartment of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USADepartment of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USADepartment of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USADepartment of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USADepartment of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USADepartment of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USADepartment of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USADepartment of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USADepartment of Pathology, Mayo Clinic, Rochester, Minnesota, USADepartment of Medicine, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, Massachusetts, USADepartment of Medicine, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, Massachusetts, USADepartment of Medicine, Division of Renal Medicine, Brigham and Women`s Hospital, Boston, Massachusetts, USADivision of Allergy and Inflammation, Beth Israel Lahey Health, Boston, Massachusetts, USABackground Non-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that biomarkers of immune dysregulationpreviously defined in patients with congenital CTLA4 deficiency, including elevated soluble interleukin-2 receptor alpha (sIL-2R) and flow cytometric cell-based markers of B and T cell dysregulation in peripheral blood may aid the diagnosis of ICI-nephritis.Methods A retrospective cohort of patients diagnosed with ICI-nephritis was compared with three prospectively enrolled control cohorts: ICI-treated controls without immune-related adverse events, patients not on ICIs with hemodynamic acute kidney injury (hemodynamic AKI), and patients not on ICIs with biopsy proven acute interstitial nephritis from other causes (non-ICI-nephritis). sIL-2R level and flow cytometric parameters were compared between groups using Wilcoxon rank sum test or Kruskal-Wallis test. Receiver operating characteristic curves were generated to define the accuracy of sIL-2R and flow cytometric biomarkers in diagnosing ICI-nephritis. The downstream impact of T cell activation in the affected kidney was investigated using archived biopsy samples to evaluate the gene expression of IL2RA, IL-2 signaling, and T cell receptor signaling in patients with ICI-nephritis compared with other causes of drug-induced nephritis, acute tubular injury, and histologically normal controls.Results sIL-2R level in peripheral blood was significantly higher in patients with ICI-nephritis (N=24) (median 2.5-fold upper limit of normal (ULN), IQR 1.9–3.3), compared with ICI-treated controls (N=10) (median 0.8-fold ULN, IQR 0.5–0.9, p<0.001) and hemodynamic AKI controls (N=6) (median 0.9-fold-ULN, IQR 0.7–1.1, p=0.008). A sIL-2R cut-off point of 1.75-fold ULN was highly diagnostic of ICI-nephritis (area under the curve >96%) when compared with either ICI-treated or hemodynamic AKI controls. By peripheral blood flow cytometry analysis, lower absolute CD8+T cells, CD45RA+CD8+ T cells, memory CD27+B cells, and expansion of plasmablasts were prominent features of ICI-nephritis compared with ICI-treated controls. Gene expressions for IL2RA, IL-2 signaling, and T cell receptor signaling in the kidney tissue with ICI-nephritis were significantly higher compared with controls.Conclusion Elevated sIL-2R level and flow cytometric markers of both B and T cell dysregulation may aid the diagnosis of ICI-nephritis.https://jitc.bmj.com/content/11/1/e006222.full |
| spellingShingle | Sandra M Herrmann Riley Fadden Ryan J Sullivan Kerry L Reynolds Harish Seethapathy Meghan E Sise Shruti Gupta Alexandra-Chloe Villani Qiyu Wang Daiana Moreno Destiny Harden R Neal Smith Ivy A Rosales Robert B Colvin Sarah Chute Lynn D Cornell Nancy J Yang Sara Barmettler Sophia Wells Jocelyn Farmer Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis Journal for ImmunoTherapy of Cancer |
| title | Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis |
| title_full | Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis |
| title_fullStr | Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis |
| title_full_unstemmed | Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis |
| title_short | Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis |
| title_sort | soluble and cell based markers of immune checkpoint inhibitor associated nephritis |
| url | https://jitc.bmj.com/content/11/1/e006222.full |
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