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

Abstract

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.

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

“…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.…”

“…In an analysis of CTCL skin samples, Querfeld et al [53] observed a higher expression of CTLA-4 on both CD4+ and CD8+ T cells. In another study no significant differences were found in CTLA-4 expression in CD4+ malignant versus bystander T cells in SS patients and healthy controls [115]. 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.…”

Monoclonal Antibodies in Dermatooncology—State of the Art and Future Perspectives

“…In an analysis of skin samples, Querfeld et al observed higher expression of CTLA-4 on both CD4+ and CD8+ T cells. In our study, we observed no significant differences in CTLA-4 expression in CD4+ malignant vs. by-stander T cells in SS patients and healthy controls [188]. There is only a limited amount of data reports on the use of anti-CTLA-4 in CTCL.…”

Blockade of programmed cell death protein 1 (PD-1) in Sézary syndrome reduces Th2 phenotype of non-tumoral T lymphocytes but may enhance tumor proliferation

“…[61][62][63][64][65][66] However, the exact role of PD-1 and its two known ligands, PD-L1 and PD-L2, in the tumor microenvironment of patients with CTCL is not fully understood and may differ from those in tumors arising from non-T cells. 36,37,42,43,[61][62][63][64][65][66][67][68] A recent single-arm, multicenter phase II study showed an overall response of 38% to pembrolizumab in patients with relapsed/refractory MF and SS (stages IB-IV; n = 24). Six out of nine responders had ≥90% improvement in skin disease as determined by mSWAT score.…”