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Single-Cell Lymphocyte Heterogeneity in Advanced Cutaneous T-cell Lymphoma Skin Tumors.

ABSTRACT: PURPOSE:The heterogeneity of tumor cells presents a major challenge to cancer diagnosis and therapy. Cutaneous T-cell lymphomas (CTCL) are a group of T lymphocyte malignancies that primarily affect skin. Lack of highly specific markers for malignant lymphocytes prevents early diagnosis, while only limited treatment options are available for patients with advanced stage CTCL. Droplet-based single-cell transcriptome analysis of CTCL skin biopsies opens avenues for dissecting patient-specific T lymphocyte heterogeneity, providing a basis for identifying specific markers for diagnosis and cure of CTCL. EXPERIMENTAL DESIGN:Single-cell RNA-sequencing was performed by Droplet-based sequencing (10X Genomics), focusing on 14,056 CD3+ lymphocytes (448 cells from normal and 13,608 cells from CTCL skin samples) from skin biopsies of 5 patients with advanced-stage CTCL and 4 healthy donors. Protein expression of identified genes was validated in advanced stage CTCL skin tumors by immunohistochemistry and confocal immunofluorescence microscopy. RESULTS:Our analysis revealed a large inter- and intratumor gene expression heterogeneity in the T lymphocyte subset, as well as a common gene expression signature in highly proliferating lymphocytes that was validated in multiple advanced-stage skin tumors. In addition, we established the immunologic state of reactive lymphocytes and found heterogeneity in effector and exhaustion programs across patient samples. CONCLUSIONS:Single-cell analysis of CTCL skin tumor samples reveals patient-specific landscapes of malignant and reactive lymphocytes within the local microenvironment of each tumor, giving an unprecedented view of lymphocyte heterogeneity and identifying tumor-specific molecular signatures, with important implications for diagnosis and personalized disease treatment.

SUBMITTER: Gaydosik AM

PROVIDER: S-EPMC6635080 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Single-Cell Lymphocyte Heterogeneity in Advanced Cutaneous T-cell Lymphoma Skin Tumors.

Gaydosik Alyxzandria M AM Tabib Tracy T Geskin Larisa J LJ Bayan Claire-Audrey CA Conway James F JF Lafyatis Robert R Fuschiotti Patrizia P

Clinical cancer research : an official journal of the American Association for Cancer Research 20190422 14

<h4>Purpose</h4>The heterogeneity of tumor cells presents a major challenge to cancer diagnosis and therapy. Cutaneous T-cell lymphomas (CTCL) are a group of T lymphocyte malignancies that primarily affect skin. Lack of highly specific markers for malignant lymphocytes prevents early diagnosis, while only limited treatment options are available for patients with advanced stage CTCL. Droplet-based single-cell transcriptome analysis of CTCL skin biopsies opens avenues for dissecting patient-specif ...[more]

PMID: 31010835

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Project description:BACKGROUND:Primary cutaneous T-cell lymphomas (CTCL) belong to the group of non-Hodgkin lymphomas and usually run an indolent course. However, some patients progress to advanced tumour or leukaemic stages. To date, there is no cure for those cases. In the last few years, several publications reported durable responses in some patients following allogeneic stem cell transplantation (alloSCT). This is an update of a Cochrane review first published in 2011 and updated in 2013. OBJECTIVES:To compare the efficacy and safety of conventional therapies with allogeneic stem cell transplantation in patients with advanced primary cutaneous T-cell lymphomas. SEARCH METHODS:We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1), MEDLINE (1950 to January 2013), Internet-databases of ongoing trials, conference proceedings of the American Society of Clinical Oncology (ASCO, 2009 to July 2013) and the American Society of Hematology (ASH, 2009 to July 2013). We also contacted members of the European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force to check for ongoing study activities. We handsearched citations from identified trials and relevant review articles. In addition, we handsearched randomised controlled trials from the European Group for Blood and Marrow Transplantation (EBMT) and International Conference on Cutaneous T-cell Lymphoma, ASCO and ASH up to July 2013. SELECTION CRITERIA:Trials eligible for inclusion were genetically randomised controlled trials (RCTs) comparing alloSCT plus conditioning therapy (regardless of agents) with conventional therapy as treatment for advanced CTCL. DATA COLLECTION AND ANALYSIS:Two review authors would have extracted data from eligible studies and assessed their quality. The primary outcome measure was overall survival; secondary outcomes were time to progression, response rate, treatment-related mortality, adverse events and quality of life. MAIN RESULTS:We did not identify any randomised controlled trials from the updated search in January 2013. In 2011, we found 2077 citations but none were relevant genetically or non-genetically randomised controlled trials. All 41 studies that were thought to be potentially suitable were excluded after full text screening for being non-randomised, not including CTCL or being review articles. AUTHORS' CONCLUSIONS:We planned to report evidence from genetically or non-genetically randomised controlled trials comparing conventional therapy and allogeneic stem cell transplantation. However, we did not identify any randomised controlled trials addressing this question. Nevertheless, prospective genetically randomised controlled trials need to be initiated to evaluate the precise role of alloSCT in advanced CTCL.

Dataset Information

Single-Cell Lymphocyte Heterogeneity in Advanced Cutaneous T-cell Lymphoma Skin Tumors.

Publications

Single-Cell Lymphocyte Heterogeneity in Advanced Cutaneous T-cell Lymphoma Skin Tumors.

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