Associate professor in immunology Faculty of Medical Sciences_UM6P Ben Guerir, Morocco
Disclosure(s):
Sanae Ben Mkaddem, PhD: No financial relationships to disclose
Introduction/Rationale: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by limited therapeutic options and poor clinical outcomes. Although immune checkpoint inhibitors (ICIs) have shown clinical benefit in a subset of TNBC patients, resistance remains common, underscoring the need for novel immunotherapeutic targets. CD160, a GPI-anchored receptor expressed on cytotoxic immune cells and endothelial cells, has recently emerged as a potential immune checkpoint in solid tumors. Here, we investigated CD160 as a dual therapeutic target in TNBC, combining immunomodulatory and anti-angiogenic functions.
Methods: Angiogenic processes were studied using primary human endothelial cells. A novel high-affinity, home-made monoclonal antibody targeting GPI-anchored CD160 was developed and used throughout the study. In vitro angiogenesis was assessed using Matrigel tube formation assays, while ex vivo vascular remodeling and angiogenesis were evaluated using aortic ring assays. Molecular interactions of CD160 were explored in endothelial cells using biochemical and imaging approaches to elucidate its signaling mechanisms.
Results: Targeting CD160 significantly inhibited pathological angiogenesis in vitro and ex vivo without inducing endothelial cytotoxicity. Anti-CD160 treatment promoted vascular normalization. These vascular effects were associated with enhanced immune cell infiltration and improved tumor perfusion. Mechanistically, CD160 was found to physically associate with LRP1 in endothelial cells, triggering autophagy-dependent pathways that contribute to angiogenic normalization.
Conclusion: Our findings identify CD160 as a novel dual-action therapeutic target in TNBC, functioning both as an immune checkpoint inhibitor and a regulator of tumor angiogenesis. CD160 targeting promotes vascular normalization through LRP1-mediated autophagy. These results support the development of CD160-directed immunotherapy as a promising strategy for TNBC treatment.
