BTLA marks a less cytotoxic T-cell subset in diffuse large B-cell lymphoma with high expression of checkpoints

Quan, Lina; Lan, Xiuwen; Meng, Yuanyuan; Guo, Xiuchen; Guo, Yiwei; Zhao, Lina; Chen, Xue; Liu, Aichun

doi:10.1016/j.exphem.2018.01.003

Cited by 36 publications

(25 citation statements)

References 38 publications

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“…Prior studies based on retrospective analysis reported a correlation between elevated expression of PD-1 and TIM-3 in CD3 + T cells with a poor response to standard chemotherapy in newly diagnosed DLBCL patients [18]. It was also reported that PD-1, TIM-3 and LAG-3 are elevated in a subset of BTLA + T cells and correlated with poor prognosis in DLBCL [29]. These studies highlight the potential interplay among multiple checkpoint molecules in the pathogenesis of lymphoma.…”

Section: Discussionmentioning

confidence: 99%

The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma

et al. 2019

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Signaling through immune checkpoint receptors may lead to T-cell exhaustion and function as immune escape mechanisms in cancer. For diffuse large B-cell lymphoma (DLBCL), the mechanistic and prognostic importance of these markers on tumor cells and the tumor microenvironment remains unclear. We determined the immunohistochemical expression of PD-1, PD-L1, TIM-3, and LAG-3 on tumor cells and on tumor infiltrating lymphocytes (TILs) among 123 DLBCL patients. TIM-3 showed positive staining on tumor cells in 39% of DLBCL cases and PD-L1 expression was noted in 15% of cases. Both PD-1 and LAG-3 were positive on tumor cells in a minority of DLBCL cases (8.3% and 7.5%, respectively), but were more widely expressed on TILs in a correlated manner. With median follow-up of 44 months ( n = 70, range 5–85), 4-year progression-free survival (PFS) and overall survival (OS) rates were significantly inferior among DLBCL patients with high vs low/negative TIM-3 expression (PFS: 23% [95% CI 7% to 46%] vs 60% [95% CI 43% to 74%], respectively, P = 0.008; OS: 30% [95% CI 10% to 53%] vs 74% [95% CI 58% to 85%], respectively, P = 0.006). Differences in OS remained significant when controlling for International Prognostic Index in Cox regression analyses (HR 3.49 [95% CI 1.40–6.15], P = 0.007). In addition, we observed that co-culture of DLBCL cell lines with primed T cells in the presence of anti-LAG-3 and anti-TIM-3 induced potent dose-dependent increases in in vitro cell death via AcellaTox and IL-2 ELISA assays, suggesting potent anti-tumor activity of these compounds.

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Section: Discussionmentioning

confidence: 99%

The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma

et al. 2019

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“…In 2017, Shen et al found that the CD8 + BTLA + T-cells isolated lymphocytes from the liver tissue of chronic hepatitis B patients had a negative regulatory effect on Treg cells that helped HBV to avoid immune clearance (29). In 2018, BTLA was elucidated as a marker of a less cytotoxic T-cell subset in diffuse large B-cell lymphoma (30). Our summary listing the research milestones on the BTLA signaling pathway in chronological order aims to distill the information from previous findings and provide more explicit research directions for future studies (Figure 1).…”

Section: Chronological Milestones In Btla Researchmentioning

confidence: 99%

BTLA/HVEM Signaling: Milestones in Research and Role in Chronic Hepatitis B Virus Infection

Zheng

Mao

et al. 2019

Front. Immunol.

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B- and T-lymphocyte attenuator (BTLA) is an immune-regulatory receptor, similar to CTLA-4 and PD-1, and is mainly expressed on B-, T-, and all mature lymphocyte cells. Herpes virus entry mediator (HVEM)-BTLA plays a critical role in immune tolerance and immune responses which are areas of intense research. However, the mechanisms of the BTLA and the BTLA/HVEM signaling pathway in human diseases remain unclear. This review describes the research milestones of BTLA and HVEM in chronological order and their role in chronic HBV infection.

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“…In tumors, BTLA ligation by herpesvirus entry mediator (HVEM) blocks T-cell activation, proliferation, and cytokine production [14]. Further, BTLA predicts poor prognosis in patients with diffuse large B cell lymphoma [15]. In inflammatory diseases, restoration of BTLA immune suppressive functionality improves multiple sclerosis [16], contact hypersensitivity [17], lupus [18] and T cell-tolerance induction to oral antigens [19].…”

Section: Introductionmentioning

confidence: 99%

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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BTLA marks a less cytotoxic T-cell subset in diffuse large B-cell lymphoma with high expression of checkpoints

Cited by 36 publications

References 38 publications

The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma

The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma

BTLA/HVEM Signaling: Milestones in Research and Role in Chronic Hepatitis B Virus Infection

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

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