Dataset Information

Peripheral T cell profiling reveals downregulated exhaustion marker and increased diversity in lymphedema post-lymphatic venous anastomosis.

ABSTRACT: Lymphedema is a progressive condition accompanying cellulitis and angiosarcoma, suggesting its association with immune dysfunction. Lymphatic venous anastomosis (LVA) can provide relief from cellulitis and angiosarcoma. However, the immune status of peripheral T cells during lymphedema and post-LVA remains poorly understood. Using peripheral blood T cells from lymphedema, post-LVA, and healthy controls (HCs), we compared the profile of T cell subsets and T cell receptor (TCR) diversity. PD-1⁺ Tim-3 ⁺ expression was downregulated in post-LVA compared with lymphedema. IFN-γ levels in CD4⁺PD-1⁺ T cells and IL-17A levels in CD4⁺ T cells were downregulated in post-LVA compared with lymphedema. TCR diversity was decreased in lymphedema compared with HCs; such TCR skewing was drastically improved in post-LVA. T cells in lymphedema were associated with exhaustion, inflammation, and diminished diversity, which were relieved post-LVA. The results provide insights into the peripheral T cell population in lymphedema and highlight the immune modulatory importance of LVA.

SUBMITTER: Imai H

PROVIDER: S-EPMC10212982 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Peripheral T cell profiling reveals downregulated exhaustion marker and increased diversity in lymphedema post-lymphatic venous anastomosis.

Imai Hirofumi H Kawase Takakazu T Yoshida Shuhei S Mese Toshiro T Roh Solji S Fujita Asuka A Uchiki Toshio T Sasaki Ayano A Nagamatsu Shogo S Takazawa Atsushi A Ichinohe Tatsuo T Koshima Isao I

iScience 20230506 6

Lymphedema is a progressive condition accompanying cellulitis and angiosarcoma, suggesting its association with immune dysfunction. Lymphatic venous anastomosis (LVA) can provide relief from cellulitis and angiosarcoma. However, the immune status of peripheral T cells during lymphedema and post-LVA remains poorly understood. Using peripheral blood T cells from lymphedema, post-LVA, and healthy controls (HCs), we compared the profile of T cell subsets and T cell receptor (TCR) diversity. PD-1<sup ...[more]

PMID: 37250774

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Project description:Exhausted T cells are effector T cells that are silenced due to continuous T cell receptor (TCR) stimulation from persistent antigens. Characteristics of exhaustion include the increased expression of multiple inhibitory receptors such as programme death-1[PD-1], lymphocyte activation gene 3 [LAG-3], T cell Ig and mucin domain [TIM-3], the loss of effector cytokine secretion and altered transcriptional profile. The PD-1/PD-L1 interaction induces functional exhaustion of tumor-reactive cytotoxic T cells and interferes with anti-tumor T cell immunity. T cell exhaustion has been observed in metastatic melanoma patients where the exhaustion of tumor specific T cells suggests that tumor clearance has been impeded and contributed to tumor immune escape. Checkpoint immunotherapies are antibodies designed to block the interaction between the inhibitory receptors expressed on T cells and their respective ligands. Therapies such as anti-PD-1 (Pembrolizumab and Nivolumab) block these inhibitory receptors and are associated with a significant improvement in overall survival and progression free survival. However, only 20-40% of metastatic melanoma patients experience long-term benefit. In a cohort of 16 metastatic melanoma patients receiving pembrolizumab, blood was serially collected before each infusion (mean 8.3; range 1-12 cycles). The presence of inhibitory markers LAG-3, TIM-3, and PD-1 on the surface of T cells was examined and assessed in relation to patient response to identify if inhibitory markers can be used to differentiate responders from non-responders for Pembrolizumab. We confirmed that across a range of cycles (range 1-26) of pembrolizumab, PD-1 expression was significantly higher on CD4+ T cells from non-responders compared to responders and TIM-3 expressed on the surface of CD8+ T cells was significantly higher in non-responders compared to responders. This longitudinal data confirms previous studies that assessed single timepoints. This study provides preliminary evidence that PD-1 and TIM-3 may be predictive of non-responders when assessed over multiple treatment cycles.

Project description:Lymphedema can be a debilitating condition, causing a great decrease in a person's quality of life (QoL). Treatment with lymphaticovenular anastomosis (LVA), in which an anastomosis is created between the lymphatic and venous system, may attenuate lymphedema symptoms and reduce swelling. In this study, we share the results using LVA to treat breast cancer-related lymphedema (BCRL) at our institution.Patients were eligible for inclusion if they suffered from unilateral BCRL, if functional lymphatics were available, if compression therapy was used for at least 6 months, and if the follow-up was 12 months at minimum. Lymph vessel functionality was assessed preoperatively using indocyanine green (ICG). During surgery, 1-3 anastomoses were created and shunt patency was confirmed using ICG. Arm volumes were measured before surgery and at 6- and 12-month follow-up. QoL was measured before surgery and at 6-month follow-up. Arm volume differences between the healthy arm and affected arm were compared between the time points.Twenty-nine consecutive female patients with unilateral BCRL were included. The preoperative mean difference in arm volumes was 701 ± 435 ml (36.9%). This was reduced to 496 ± 302 ml (24.7%) at 6-month follow-up (p = 0.00). At 12-month follow-up, the mean difference in arm volume was 467 ± 303 ml (23.5%) (p = 0.02). The overall perceived QoL was increased from 5.8 ± 1.1 to 7.4 ± 0.7 (p = 0.00). The functionality score decreased from 2.2 to 1.8 (p = 0.00), the appearance score decreased from 2.6 to 1.9 (p = 0.00), the symptoms score decreased from 2.8 to 1.8 (p = 0.00), and the mood score decreased from 2.7 to 1.5 (p = 0.00). Fifteen patients (53.6%) were able to discontinue the use of compression garment.Treatment with LVAs is effective in reducing arm volume difference in patients suffering from BCRL. Although no complete reduction of the edema was achieved at 12-month follow-up, the procedure significantly increased the patients' QoL.

Dataset Information

Peripheral T cell profiling reveals downregulated exhaustion marker and increased diversity in lymphedema post-lymphatic venous anastomosis.

Publications

Peripheral T cell profiling reveals downregulated exhaustion marker and increased diversity in lymphedema post-lymphatic venous anastomosis.

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