BTLA and HVEM Pathway

Introduction

BTLA is a novel checkpoint co-inhibitory receptor belonging to the CD28 superfamily, which appears on a wide range of immune cells, including T, B, NK, and other cells. Herpesvirus entry mediator (HVEM) is identified as the BTLA ligand. However, BTLA is not the unique binding partner for HVEM; it competes with LIGHT and lymphotoxin-α, as well as CD160 for binding to HVEM.

HVEM works as a bidirectional switch with both co-stimulatory and co-inhibitory functions. The binding of HVEM to BTLA and CD160 exerts an adverse regulatory effect, inhibiting T- and B-lymphocyte activation and proliferation and cytokine production. However, LIGHT-HVEM binding promotes bi-directional co-stimulation of immune effector responses. Therefore, the HVEM-LIGHT and HVEM-BTLA-CD160 network is a self-regulating ligand/receptor system that delivers bidirectional survival, proinflammatory, and inhibitory signals to T cells, NKT cells, and other immune cells. Tumor cells exploit the BTLA-HVEM pathway by either promoting the formation of dysfunctional T cells that persistently express BTLA and render them susceptible to inactivation or by expressing HVEM, as it has been found with melanoma. The increased BTLA and HVEM levels correlate with the development and poor prognosis of cancers. Thus, the BTLA-HVEM pathway is being considered as a new target for checkpoint blockade.

Preclinical and Clinical Development of Drugs for BTLA and HVEM Pathway

Since the discovery of BTLA in 2003, multiple studies have established that the HVEM-BTLA signaling pathway plays an essential immunomodulatory role in autoimmune disease, cancer, transplantation, infection, and other conditions. Recently, targeted anticancer drugs for the HVEM-BTLA pathway are emerging, and anti-BTLA antibodies have shown effective antitumor activity in melanoma and mammary carcinoma models. BTLA and HVEM might be novel prognostic indicators, and the BTLA/HVEM pathway is considered a promising therapeutic target for cancer immunotherapy.

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