TIGIT and Helios Are Highly Expressed on CD4+ T Cells in Sézary Syndrome Patients

Jariwala, Neha; Benoit, Bernice M.; Kossenkov, Andrew V.; Oetjen, Landon K.; Whelan, Timothy M.; Cornejo, Christine; Takeshita, Junko; Kim, Brian; Showe, Louise C.; Wysocka, Maria; Rook, Alain H.

doi:10.1016/j.jid.2016.08.016

Cited by 22 publications

(22 citation statements)

References 15 publications

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“…In parallel, we further found increased FCRL3 and TIGIT expression in SS tumor cells. These results are in line with the work of Jariwala et al documenting the high expression of FRCL3 and TIGIT on CD4þ SS cells [40]. Also, Wysocka et al reported FCRL3 expression in patients with high tumor burden [41].…”

Section: Discussionsupporting

confidence: 90%

“…Also, Wysocka et al reported FCRL3 expression in patients with high tumor burden [41]. In these studies, TIGIT and/or FCRL3 expression showed a correlation with an increase in single TCRVb þ CD4 þ cells or loss of CD26 expression [40]. However, in our patients' cohort, both TIGIT and FCRL3 were found to be similarly upregulated on both tumor and bystander CD4þ T-cells, despite a distinct trend for the higher expression of BTLA and TIGIT in clonal cells.…”

Section: Discussionmentioning

confidence: 86%

“…In CTCL, the role of immunosuppressive pathways and the expression of checkpoint molecules on tumor and especially non-tumor T cells is unclear. Preliminary data suggest enhanced FCRL3, TIGIT, and LAG-3 expression on tumor T-cells [39][40][41][42]. BLTA-expression in T-cells from CTCL patients has not been investigated thus far.…”

Section: Introductionmentioning

confidence: 99%

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Divergent LAG-3 versus BTLA, TIGIT, and FCRL3 expression in Sézary syndrome

Anzengruber

Ignatova

Schlaepfer

et al. 2019

Leukemia & Lymphoma

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In S ezary syndrome (SS) impaired T-cell function and cytokine profile lead to immune evasion. Immune checkpoints non-redundantly regulate immune responses and targeting them is promising. We evaluated the expression of BTLA, CTLA-4, FCRL3, LAG-3, and TIGIT in tumor and nontumor SS T-cells.Compared to CD4þ T helper cells from ten healthy individuals, tumor cells of eight SS patients had a significant upregulation of BTLA (1.5-fold; p < .0001), FRCL3 (2.2-fold; p < .0028) and TIGIT (2.2-fold; p < .0003) expression. In contrast, we found a reduced expression of LAG-3þ cells in the blood of tumor patients (0.5-fold; p < .0014). Only weak alternations between tumor, non-tumor cells, and healthy controls were observed regarding CTLA-4 (0.5-fold; p < .2022). Our results show a diverse expression pattern of immune-regulatory molecules in SS patients. As these molecules are essential in the regulation of T-cell mediated tumor surveillance and defense, their specific targeting might be of clinical relevance.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 86%

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Divergent LAG-3 versus BTLA, TIGIT, and FCRL3 expression in Sézary syndrome

Anzengruber

Ignatova

Schlaepfer

et al. 2019

Leukemia & Lymphoma

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“…TIGIT expression by CD4 þ T cells from the peripheral blood of patients with advanced stage Sezary syndrome was recently associated with reduced IFNG and IL2 production (44). We found that TIGIT is also highly expressed by both CD8 þ and CD4 þ TILs from advanced stage CTCL skin tumors, and in parallel with expression of other coinhibitory receptors, most notably TIM3, PD1, LAG3, and to a lesser extent CTLA4.…”

Section: Discussionsupporting

confidence: 51%

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

Gaydosik

Tabib

Geskin

et al. 2019

Clinical Cancer Research

101

130

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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 þ 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.

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“…However, as the combination of anti-PD-1 (nivolumab) with anti-CTLA-4 showed no benefit compared to nivolumab alone [116], there are no active or recruiting clinical studies testing the efficacy of CTLA-4 targeting in CTCL. A recent analysis [115] of a panel of checkpoint inhibitors in a small cohort of SS patients revealed a significant upregulation of FRCL3 and TIGIT expression, which is in line with the previous reports [117,118], together with a reduced expression of LAG-3 on CD4+ tumor cells. As several advanced clinical studies address TIGIT as a target molecule, it may also be of interest in CTCL.…”

Section: Immune Checkpoint Inhibitorssupporting

confidence: 88%

Pathogenesis and Therapy of Primary Cutaneous T-Cell Lymphoma: Collegium Internationale Allergologicum (CIA) Update 2020

Bobrowicz

Fassnacht

Ignatova

et al. 2020

Int Arch Allergy Immunol

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Cutaneous T-cell lymphoma (CTCL) is a heterogeneous disease group of unknown etiology with a complex immunological background. As CTCL arises from T cells that have a vital role in the antitumor response, their therapy is largely aimed at reversing the immunological mechanisms leading to or manifesting during this malignancy. Early disease stages can be controlled with skin-directed therapy in most CTCL cases. Still, advanced CTCL has a dismal prognosis and warrants systemic therapy. Despite considerable progress in understanding the pathophysiology of the disease and the numerous systemic treatment options available, longterm remission rates with conventional treatments alone are still low. Allogeneic hematopoietic stem cell transplantation is currently the only curative option for advanced CTCL, including mycosis fungoides and Sézary syndrome. The aims of this review is to summarize the recent findings on the immunology of this heterogeneous disease and to present the advances in its clinical management.

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TIGIT and Helios Are Highly Expressed on CD4+ T Cells in Sézary Syndrome Patients

Cited by 22 publications

References 15 publications

Divergent LAG-3 versus BTLA, TIGIT, and FCRL3 expression in Sézary syndrome

Divergent LAG-3 versus BTLA, TIGIT, and FCRL3 expression in Sézary syndrome

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

Pathogenesis and Therapy of Primary Cutaneous T-Cell Lymphoma: Collegium Internationale Allergologicum (CIA) Update 2020

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