Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapy
Although immune checkpoint inhibitor (ICI) therapy has dramatically improved outcome for metastatic melanoma patients, many patients do not benefit. Since adverse events may be severe, biomarkers for resistance would be valuable, especially in the adjuvant setting. We performed high-plex digital spa...
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Taylor & Francis Group
2023-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2260618 |
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| author | Sandra Martinez-Morilla Myrto Moutafi Aileen I. Fernandez Shlomit Jessel Prajan Divakar Pok Fai Wong Rolando Garcia-Milian Kurt A. Schalper Harriet M. Kluger David L. Rimm |
| author_facet | Sandra Martinez-Morilla Myrto Moutafi Aileen I. Fernandez Shlomit Jessel Prajan Divakar Pok Fai Wong Rolando Garcia-Milian Kurt A. Schalper Harriet M. Kluger David L. Rimm |
| author_sort | Sandra Martinez-Morilla |
| collection | DOAJ |
| description | Although immune checkpoint inhibitor (ICI) therapy has dramatically improved outcome for metastatic melanoma patients, many patients do not benefit. Since adverse events may be severe, biomarkers for resistance would be valuable, especially in the adjuvant setting. We performed high-plex digital spatial profiling (DSP) using the NanoString GeoMx® on 53 pre-treatment specimens from ICI-treated metastatic melanoma cases. We interrogated 77 targets simultaneously in four molecular compartments defined by S100B for tumor, CD68 for macrophages, CD45 for leukocytes, and nonimmune stromal cells defined as regions negative for all three compartment markers but positive for SYTO 13. For DSP validation, we confirmed the results obtained for some immune markers, such as CD8, CD4, CD20, CD68, CD45, and PD-L1, by quantitative immunofluorescence (QIF). In the univariable analysis, 38 variables were associated with outcome, 14 of which remained significant after multivariable adjustment. Among them, CD95 was further validated using multiplex immunofluorescence in the Discovery immunotherapy (ITX) Cohort and an independent validation cohort with similar characteristics, showing an association between high levels of CD95 and shorter progression-free survival. We found that CD95 in stroma was associated with resistance to ICI. With further validation, this biomarker could have value to select patients that will not benefit from immunotherapy. |
| format | Article |
| id | doaj-art-61850931c801456bb2e5a14b003e557a |
| institution | Kabale University |
| issn | 2162-402X |
| language | English |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-61850931c801456bb2e5a14b003e557a2024-12-27T17:34:39ZengTaylor & Francis GroupOncoImmunology2162-402X2023-12-0112110.1080/2162402X.2023.2260618Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapySandra Martinez-Morilla0Myrto Moutafi1Aileen I. Fernandez2Shlomit Jessel3Prajan Divakar4Pok Fai Wong5Rolando Garcia-Milian6Kurt A. Schalper7Harriet M. Kluger8David L. Rimm9Department of Pathology, Yale School of Medicine, New Haven, CT, USADepartment of Pathology, Yale School of Medicine, New Haven, CT, USADepartment of Pathology, Yale School of Medicine, New Haven, CT, USASection of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USANanoString Technologies, Seattle, WA, USADepartment of Pathology, Yale School of Medicine, New Haven, CT, USABioinformatics Support Program, Cushing/Whitney Medical Library, Yale School of Medicine, New Haven, CT, USADepartment of Pathology, Yale School of Medicine, New Haven, CT, USASection of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USADepartment of Pathology, Yale School of Medicine, New Haven, CT, USAAlthough immune checkpoint inhibitor (ICI) therapy has dramatically improved outcome for metastatic melanoma patients, many patients do not benefit. Since adverse events may be severe, biomarkers for resistance would be valuable, especially in the adjuvant setting. We performed high-plex digital spatial profiling (DSP) using the NanoString GeoMx® on 53 pre-treatment specimens from ICI-treated metastatic melanoma cases. We interrogated 77 targets simultaneously in four molecular compartments defined by S100B for tumor, CD68 for macrophages, CD45 for leukocytes, and nonimmune stromal cells defined as regions negative for all three compartment markers but positive for SYTO 13. For DSP validation, we confirmed the results obtained for some immune markers, such as CD8, CD4, CD20, CD68, CD45, and PD-L1, by quantitative immunofluorescence (QIF). In the univariable analysis, 38 variables were associated with outcome, 14 of which remained significant after multivariable adjustment. Among them, CD95 was further validated using multiplex immunofluorescence in the Discovery immunotherapy (ITX) Cohort and an independent validation cohort with similar characteristics, showing an association between high levels of CD95 and shorter progression-free survival. We found that CD95 in stroma was associated with resistance to ICI. With further validation, this biomarker could have value to select patients that will not benefit from immunotherapy.https://www.tandfonline.com/doi/10.1080/2162402X.2023.2260618BiomarkersDSPimmunotherapymelanoma |
| spellingShingle | Sandra Martinez-Morilla Myrto Moutafi Aileen I. Fernandez Shlomit Jessel Prajan Divakar Pok Fai Wong Rolando Garcia-Milian Kurt A. Schalper Harriet M. Kluger David L. Rimm Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapy OncoImmunology Biomarkers DSP immunotherapy melanoma |
| title | Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapy |
| title_full | Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapy |
| title_fullStr | Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapy |
| title_full_unstemmed | Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapy |
| title_short | Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapy |
| title_sort | digital spatial profiling of melanoma shows cd95 expression in immune cells is associated with resistance to immunotherapy |
| topic | Biomarkers DSP immunotherapy melanoma |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2260618 |
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