The CD160–HVEM axis at the crossroads of tolerance and immunity: lessons from cancer for autoimmunity and transplantation
- 1Department of Urology, Peking University Third Hospital
Abstract
Background: The clinical success of immune checkpoint blockade (ICB) in oncology has validated the existence of molecular brakes that restrain T-cell immunity. While releasing these brakes unleashes antitumour responses, their physiological role is to maintain self-tolerance. This review explores the reciprocal paradigm of the CD160–HVEM axis across three disease settings: immuno-oncology, autoimmunity and transplantation. CD160–HVEM signalling can enforce pathological T-cell exhaustion in cancer, yet its failure or costimulatory co-option can precipitate autoimmunity or accelerate allograft rejection.
Mechanisms: Unlike programmed cell death protein 1 (PD-1), CD160 operates within a bidirectional network involving herpesvirus entry mediator (HVEM; TNFRSF14), B- and T-lymphocyte attenuator (BTLA) and LIGHT (TNFSF14). The axis is expressed across lymphocytes, myeloid cells, epithelium, endothelium and malignant B cells. Mouse and human biology of the axis are not interchangeable: murine CD160 is a broad major histocompatibility complex (MHC) class I and CD1d receptor, whereas human natural killer (NK) triggering is dominated by HLA-C, and the transmembrane isoform CD160-TM is human-characterised. Structural diversity, from an inhibitory glycosylphosphatidylinositol (GPI)-anchored form to activating CD160-TM on NK cells, positions CD160 as a tunable rheostat rather than a linear checkpoint.
Therapeutic implications: While direct anti-CD160 candidates remain in advanced preclinical development, other components of the HVEM network are undergoing human clinical testing. The most mature clinical programme is tifcemalimab, an anti-BTLA monoclonal antibody, not an anti-CD160 agent. Antagonistic anti-HVEM antibodies (Demerlé anti-HVEM18–10 in humanised mice; preclinical fully human 4CB1, mechanistically related but distinct) block HVEM engagement by both BTLA and CD160. Because CD160 is inhibitory on T cells but activating on NK cells via CD160-TM, a systemic antibody to the shared ectodomain is a dual-function drug-design constraint, not a simple checkpoint blockade.
Conclusion: Precision use of this axis requires isoform, cell type, interaction geometry and disease context to be specified before a direction of intervention is chosen. Next steps are biomarker-qualified enrichment, isoform-discriminating reagents, and correlative CD160 profiling inside ongoing BTLA–HVEM studies. Pathological exhaustion that shields tumours remains a map for restoring tolerance in autoimmunity and for blocking CD28-independent rejection in transplantation.
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BibTeX
@article{sun2026cd160hvem,
title = {{The CD160–HVEM axis at the crossroads of tolerance and immunity: lessons from cancer for autoimmunity and transplantation}},
author = {Shulin Sun and Lulin Ma},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1782124},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1782124/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The CD160–HVEM axis at the crossroads of tolerance and immunity: lessons from cancer for autoimmunity and transplantation
AU - Shulin Sun
AU - Lulin Ma
PY - 2026
DA - 2026/10/06
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1782124
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1782124/full
AB - Background: The clinical success of immune checkpoint blockade (ICB) in oncology has validated the existence of molecular brakes that restrain T-cell immunity. While releasing these brakes unleashes antitumour responses, their physiological role is to maintain self-tolerance. This review explores the reciprocal paradigm of the CD160–HVEM axis across three disease settings: immuno-oncology, autoimmunity and transplantation. CD160–HVEM signalling can enforce pathological T-cell exhaustion in cancer, yet its failure or costimulatory co-option can precipitate autoimmunity or accelerate allograft rejection. Mechanisms: Unlike programmed cell death protein 1 (PD-1), CD160 operates within a bidirectional network involving herpesvirus entry mediator (HVEM; TNFRSF14), B- and T-lymphocyte attenuator (BTLA) and LIGHT (TNFSF14). The axis is expressed across lymphocytes, myeloid cells, epithelium, endothelium and malignant B cells. Mouse and human biology of the axis are not interchangeable: murine CD160 is a broad major histocompatibility complex (MHC) class I and CD1d receptor, whereas human natural killer (NK) triggering is dominated by HLA-C, and the transmembrane isoform CD160-TM is human-characterised. Structural diversity, from an inhibitory glycosylphosphatidylinositol (GPI)-anchored form to activating CD160-TM on NK cells, positions CD160 as a tunable rheostat rather than a linear checkpoint. Therapeutic implications: While direct anti-CD160 candidates remain in advanced preclinical development, other components of the HVEM network are undergoing human clinical testing. The most mature clinical programme is tifcemalimab, an anti-BTLA monoclonal antibody, not an anti-CD160 agent. Antagonistic anti-HVEM antibodies (Demerlé anti-HVEM18–10 in humanised mice; preclinical fully human 4CB1, mechanistically related but distinct) block HVEM engagement by both BTLA and CD160. Because CD160 is inhibitory on T cells but activating on NK cells via CD160-TM, a systemic antibody to the shared ectodomain is a dual-function drug-design constraint, not a simple checkpoint blockade. Conclusion: Precision use of this axis requires isoform, cell type, interaction geometry and disease context to be specified before a direction of intervention is chosen. Next steps are biomarker-qualified enrichment, isoform-discriminating reagents, and correlative CD160 profiling inside ongoing BTLA–HVEM studies. Pathological exhaustion that shields tumours remains a map for restoring tolerance in autoimmunity and for blocking CD28-independent rejection in transplantation.
SN - 1664-3224
ER -