JAML immunotherapy targets recently activated tumor-infiltrating CD8+ T cells

• Published in: Cell reports (Cambridge) 2023-02, Vol.42 (2), p.112040-112040, Article 112040
• Main Authors: Eschweiler, Simon, Wang, Alice, Ramírez-Suástegui, Ciro, von Witzleben, Adrian, Li, Yingcong, Chee, Serena J., Simon, Hayley, Mondal, Monalisa, Ellis, Matthew, Thomas, Gareth J., Chandra, Vivek, Ottensmeier, Christian H., Vijayanand, Pandurangan
• Format: Article
• Language: English
• Subjects: agonistic antibody; cancer immunotherapy; co-stimulatory molecule; CP: Cancer; CP: Immunology; JAML; TRM cells; tumor immunology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112040

Junctional adhesion molecule-like protein (JAML) serves as a co-stimulatory molecule in γδ T cells. While it has recently been described as a cancer immunotherapy target in mice, its potential to cause toxicity, specific mode of action with regard to its cellular targets, and whether it can be targeted in humans remain unknown. Here, we show that JAML is induced by T cell receptor engagement, reveal that this induction is linked to cis-regulatory interactions between the CD3D and JAML gene loci. When compared with other immunotherapy targets plagued by low target specificity and end-organ toxicity, we find JAML to be mostly restricted to and highly expressed by tissue-resident memory CD8+ T cells in multiple cancer types. By delineating the key cellular targets and functional consequences of agonistic anti-JAML therapy in a murine melanoma model, we show its specific mode of action and the reason for its synergistic effects with anti-PD-1. [Display omitted] •JAML is a co-stimulatory molecule in human and murine αβ T cells•JAML is induced by TCR stimulation and enriched in tumor-infiltrating TRM cells•JAML expression in TRM cells is associated with better survival outcomes in HNSCC•Agonistic anti-JAML controls tumor growth and synergizes with anti-PD-1 therapy Eschweiler et al. identify JAML as a promising immunotherapy target with low on-target/off-cell and on-target/off-tumor effects. When compared with other immunotherapy targets plagued by low target specificity and end-organ toxicity, they find JAML to be mostly restricted to and highly expressed by (tissue-resident) CD8+ T cells in multiple cancer types.