Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases
Background The tumor microenvironment (TME) contributes to cancer progression and treatment response to therapy, including in renal cell carcinoma (RCC). Prior profiling studies, including single-cell transcriptomics, often involve limited sample sizes and lack spatial orientation. The TME of RCC br...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/8/e007240.full |
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| author | Wei Wei Michael Hurwitz Sabina Signoretti Lucia Jilaveanu Toni K Choueiri David L Rimm Adebowale Adeniran Sandra Martínez Harriet M Kluger David A Schoenfeld Myrto Moutafi Dijana Djureinovic Ross D Merkin David A Braun Fabio Parisi |
| author_facet | Wei Wei Michael Hurwitz Sabina Signoretti Lucia Jilaveanu Toni K Choueiri David L Rimm Adebowale Adeniran Sandra Martínez Harriet M Kluger David A Schoenfeld Myrto Moutafi Dijana Djureinovic Ross D Merkin David A Braun Fabio Parisi |
| author_sort | Wei Wei |
| collection | DOAJ |
| description | Background The tumor microenvironment (TME) contributes to cancer progression and treatment response to therapy, including in renal cell carcinoma (RCC). Prior profiling studies, including single-cell transcriptomics, often involve limited sample sizes and lack spatial orientation. The TME of RCC brain metastases, a major cause of morbidity, also remains largely uncharacterized.Methods We performed digital spatial profiling on the NanoString GeoMx platform using 52 validated immuno-oncology markers on RCC tissue microarrays representing progressive stages of RCC, including brain metastases. We profiled 76 primary tumors, 27 adjacent histologically normal kidney samples, and 86 metastases, including 24 brain metastases.Results We observed lower immune checkpoint (TIM-3 and CTLA-4), cytolytic (GZMA and GZMB), and T cell activation (CD25) protein expression in metastases compared with primary tumors in two separate cohorts. We also identified changes in macrophages in metastases, with brain metastases-susceptible patients showing less M1-like, inflammatory macrophage markers (HLA-DR and CD127) in metastatic samples. A comparison of brain metastases to extracranial metastases revealed higher expression of the anti-apoptotic, BCL-2-family protein BCL-XL and lower expression of the innate immune activator STING in brain metastases. Lower TIM-3 and CD40 in the TME of brain metastases appear to be associated with longer survival, a finding that requires further validation.Conclusions Compared with primary tumors, RCC metastases, including brain metastases, express lower levels of numerous markers of immune activation and current or investigational therapeutic targets. Our findings may have important implications for designing future biomarker and treatment studies and may aid in development of brain metastases-specific therapies. |
| format | Article |
| id | doaj-art-9b38124075304f5f862a35be425f0ea0 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-9b38124075304f5f862a35be425f0ea02025-02-09T02:00:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-08-0111810.1136/jitc-2023-007240Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastasesWei Wei0Michael Hurwitz1Sabina Signoretti2Lucia Jilaveanu3Toni K Choueiri4David L Rimm5Adebowale Adeniran6Sandra Martínez7Harriet M Kluger8David A Schoenfeld9Myrto Moutafi10Dijana Djureinovic11Ross D Merkin12David A Braun13Fabio Parisi14AbCellera, Vancouver, BC, CanadaMedical Oncology, Yale School of Medicine, New Haven, Connecticut, USA6Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USASchool of Medical Oncology, Yale School of Medicine, New Haven, Connecticut, USA7Dana-Farber Cancer Institute, Boston, MA, USADepartment of Pathology, Yale University School of Medicine, New Haven, Connecticut, USADepartment of Pathology, Yale School of Medicine, New Haven, Connecticut, USADepartment of Pathology, Yale School of Medicine, New Haven, Connecticut, USADepartment of Medical Oncology, Yale School of Medicine, New Haven, Connecticut, USASchool of Medical Oncology, Yale School of Medicine, New Haven, Connecticut, USADepartment of Pathology, Yale School of Medicine, New Haven, Connecticut, USADepartment of Medical Oncology, Yale School of Medicine, New Haven, Connecticut, USASchool of Medical Oncology, Yale School of Medicine, New Haven, Connecticut, USA1Dana-Farber Cancer Institute, Boston, MA, USASchool of Medical Oncology, Yale School of Medicine, New Haven, Connecticut, USABackground The tumor microenvironment (TME) contributes to cancer progression and treatment response to therapy, including in renal cell carcinoma (RCC). Prior profiling studies, including single-cell transcriptomics, often involve limited sample sizes and lack spatial orientation. The TME of RCC brain metastases, a major cause of morbidity, also remains largely uncharacterized.Methods We performed digital spatial profiling on the NanoString GeoMx platform using 52 validated immuno-oncology markers on RCC tissue microarrays representing progressive stages of RCC, including brain metastases. We profiled 76 primary tumors, 27 adjacent histologically normal kidney samples, and 86 metastases, including 24 brain metastases.Results We observed lower immune checkpoint (TIM-3 and CTLA-4), cytolytic (GZMA and GZMB), and T cell activation (CD25) protein expression in metastases compared with primary tumors in two separate cohorts. We also identified changes in macrophages in metastases, with brain metastases-susceptible patients showing less M1-like, inflammatory macrophage markers (HLA-DR and CD127) in metastatic samples. A comparison of brain metastases to extracranial metastases revealed higher expression of the anti-apoptotic, BCL-2-family protein BCL-XL and lower expression of the innate immune activator STING in brain metastases. Lower TIM-3 and CD40 in the TME of brain metastases appear to be associated with longer survival, a finding that requires further validation.Conclusions Compared with primary tumors, RCC metastases, including brain metastases, express lower levels of numerous markers of immune activation and current or investigational therapeutic targets. Our findings may have important implications for designing future biomarker and treatment studies and may aid in development of brain metastases-specific therapies.https://jitc.bmj.com/content/11/8/e007240.full |
| spellingShingle | Wei Wei Michael Hurwitz Sabina Signoretti Lucia Jilaveanu Toni K Choueiri David L Rimm Adebowale Adeniran Sandra Martínez Harriet M Kluger David A Schoenfeld Myrto Moutafi Dijana Djureinovic Ross D Merkin David A Braun Fabio Parisi Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases Journal for ImmunoTherapy of Cancer |
| title | Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases |
| title_full | Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases |
| title_fullStr | Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases |
| title_full_unstemmed | Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases |
| title_short | Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases |
| title_sort | immune dysfunction revealed by digital spatial profiling of immuno oncology markers in progressive stages of renal cell carcinoma and in brain metastases |
| url | https://jitc.bmj.com/content/11/8/e007240.full |
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