BTLA identifies dysfunctional PD-1-expressing CD4⁺ T cells in human hepatocellular carcinoma

Abstract

Although immunotherapy targeting programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway is being applied in clinic, the response outcomes are heterogeneous, suggesting existences of distinctive subsets within PD-1-expressing T cells that react differently to PD-1/PD-L1 blockade. However, markers to demarcate these subsets in human cancers remain unclear. Here, we found that both PD-1 and B and T lymphocyte attenuator (BTLA) were significantly upregulated on CD4 C T cells from tumor compared with those from paired non-tumor liver in hepatocellular carcinoma (HCC) patients. Interestingly, over 85% BTLA C T cell function in HCC. In conclusion, BTLA could identify distinct function of PD-1 expressing CD4 C T cells in human cancer, which might not only advance our understanding of inhibitory receptor blockade, but also provide new targets for clinical predictors of response to these immunotherapies.

Immune-based therapies for hepatocellular carcinoma

“…Other drivers of T-cell exhaustion in HCC include LAG-3, associated to hypofunctional CD8+ responses in HCC TILs, which can be reversed upon LAG-3 blockade [53] and B and T-lymphocyte attenuator (BTLA), seen in >50% of PD-1+ TILs in HCC and denoting particularly pronounced hypo-functionality [54] and T-cell exclusion [55].…”

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

“…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]. High BTLA expression is a hallmark of anergic and dysfunctional T cells [17,20].…”

BTLA and PD-1 employ distinct phosphatases to differentially repress T cell signaling

“…In addition, combination blockade of PD-1 and BTLA leads to superior T cell proliferation and cytokine production than mono-blockade of PD-1 (Stecher et al, 2017). Further, BTLA/PD-1 co-expression is required for the exhaustion of human hepatocellular carcinoma infiltrated CD4 + T cells (Zhao et al, 2016), consistent with an important role of BTLA in repressing the anti-tumor activity of T cells.…”