دورية أكاديمية
The Tumor Immune Landscape and Architecture of Tertiary Lymphoid Structures in Urothelial Cancer.
| العنوان: | The Tumor Immune Landscape and Architecture of Tertiary Lymphoid Structures in Urothelial Cancer. |
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| المؤلفون: | van Dijk N; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands., Gil-Jimenez A; Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, Netherlands.; Oncode Institute, Utrecht, Netherlands., Silina K; Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland., van Montfoort ML; Department of Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands., Einerhand S; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands., Jonkman L; Department of Medical Oncology, Maastricht University Medical Center, Maastricht, Netherlands., Voskuilen CS; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands., Peters D; Core Facility Molecular Pathology & Biobanking, The Netherlands Cancer Institute, Amsterdam, Netherlands., Sanders J; Department of Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands., Lubeck Y; Department of Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands., Broeks A; Core Facility Molecular Pathology & Biobanking, The Netherlands Cancer Institute, Amsterdam, Netherlands., Hooijberg E; Department of Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands., Vis DJ; Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, Netherlands.; Oncode Institute, Utrecht, Netherlands., van den Broek M; Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland., Wessels LFA; Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, Netherlands.; Oncode Institute, Utrecht, Netherlands.; Department of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, Delft, Netherlands., van Rhijn BWG; Department of Urology, The Netherlands Cancer Institute, Amsterdam, Netherlands.; Department of Urology, Caritas St. Josef Medical Center, University of Regensburg, Regensburg, Germany., van der Heijden MS; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands.; Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, Netherlands. |
| المصدر: | Frontiers in immunology [Front Immunol] 2021 Dec 20; Vol. 12, pp. 793964. Date of Electronic Publication: 2021 Dec 20 (Print Publication: 2021). |
| نوع المنشور: | Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Lausanne : Frontiers Research Foundation] |
| مواضيع طبية MeSH: | CD8-Positive T-Lymphocytes/*immunology , Immune Checkpoint Inhibitors/*therapeutic use , Ipilimumab/*therapeutic use , Nivolumab/*therapeutic use , T-Lymphocytes, Helper-Inducer/*immunology , Urothelium/*metabolism, Aged ; CTLA-4 Antigen/antagonists & inhibitors ; Cell Differentiation ; Cells, Cultured ; Female ; Fluorescent Antibody Technique ; Forkhead Transcription Factors/metabolism ; Humans ; Immunotherapy ; Lymphocyte Activation ; Male ; Middle Aged ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Programmed Cell Death 1 Receptor/metabolism ; Tertiary Lymphoid Structures ; Treatment Outcome ; Tumor Microenvironment ; Urologic Neoplasms ; Urothelium/pathology |
| مستخلص: | Candidate immune biomarkers have been proposed for predicting response to immunotherapy in urothelial cancer (UC). Yet, these biomarkers are imperfect and lack predictive power. A comprehensive overview of the tumor immune contexture, including Tertiary Lymphoid structures (TLS), is needed to better understand the immunotherapy response in UC. We analyzed tumor sections by quantitative multiplex immunofluorescence to characterize immune cell subsets in various tumor compartments in tumors without pretreatment and tumors exposed to preoperative anti-PD1/CTLA-4 checkpoint inhibitors (NABUCCO trial). Pronounced immune cell presence was found in UC invasive margins compared to tumor and stroma regions. CD8 + PD1 + T-cells were present in UC, particularly following immunotherapy. The cellular composition of TLS was assessed by multiplex immunofluorescence (CD3, CD8, FoxP3, CD68, CD20, PanCK, DAPI) to explore specific TLS clusters based on varying immune subset densities. Using a k-means clustering algorithm, we found five distinct cellular composition clusters. Tumors unresponsive to anti-PD-1/CTLA-4 immunotherapy showed enrichment of a FoxP3 + T-cell-low TLS cluster after treatment. Additionally, cluster 5 (macrophage low) TLS were significantly higher after pre-operative immunotherapy, compared to untreated tumors. We also compared the immune cell composition and maturation stages between superficial (submucosal) and deeper TLS, revealing that superficial TLS had more pronounced T-helper cells and enrichment of early TLS than TLS located in deeper tissue. Furthermore, superficial TLS displayed a lower fraction of secondary follicle like TLS than deeper TLS. Taken together, our results provide a detailed quantitative overview of the tumor immune landscape in UC, which can provide a basis for further studies. Competing Interests: MH received research funding from Bristol Myers Squibb, AstraZeneca, 4SC and Roche, and consultancy fees from Bristol Myers Squibb, Roche, Merck Sharp & Dohme, Merck, AstraZeneca, Pfizer, Janssen and Seattle Genetics which were all paid to the Netherlands Cancer Institute. LW received research funding from Genmab. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Dijk, Gil-Jimenez, Silina, Montfoort, Einerhand, Jonkman, Voskuilen, Peters, Sanders, Lubeck, Broeks, Hooijberg, Vis, Broek, Wessels, Rhijn and Heijden.) |
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| فهرسة مساهمة: | Keywords: bladder cancer; immunotherapy; multiplex immunofluorescence; tertiary lymphoid structures (TLS); tumor microenvironment; urothelial cancer |
| المشرفين على المادة: | 0 (CTLA-4 Antigen) 0 (FOXP3 protein, human) 0 (Forkhead Transcription Factors) 0 (Immune Checkpoint Inhibitors) 0 (Ipilimumab) 0 (PDCD1 protein, human) 0 (Programmed Cell Death 1 Receptor) 31YO63LBSN (Nivolumab) |
| تواريخ الأحداث: | Date Created: 20220106 Date Completed: 20220225 Latest Revision: 20220225 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC8721669 |
| DOI: | 10.3389/fimmu.2021.793964 |
| PMID: | 34987518 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1664-3224 |
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| DOI: | 10.3389/fimmu.2021.793964 |