JAML immunotherapy targets recently activated tumor-infiltrating CD8+ T cells
Simon Eschweiler,
Alice Wang,
Ciro Ramírez-Suástegui,
Adrian von Witzleben,
Yingcong Li,
Serena J. Chee,
Hayley Simon,
Monalisa Mondal,
Matthew Ellis,
Gareth J. Thomas,
Vivek Chandra,
Christian H. Ottensmeier,
Pandurangan Vijayanand
Affiliations
Simon Eschweiler
La Jolla Institute for Immunology, La Jolla, CA, USA
Alice Wang
La Jolla Institute for Immunology, La Jolla, CA, USA
Ciro Ramírez-Suástegui
La Jolla Institute for Immunology, La Jolla, CA, USA
Adrian von Witzleben
Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
Yingcong Li
La Jolla Institute for Immunology, La Jolla, CA, USA; University of California San Diego, La Jolla, CA, USA
Serena J. Chee
Department of Molecular and Clinical Cancer Medicine and NIHR and CRUK Liverpool Experimental Cancer Medicine Center, University of Liverpool, Liverpool, UK; Department of Respiratory Medicine, Liverpool Heart and Chest Hospital and NHS Foundation Trust, Liverpool, UK
Hayley Simon
La Jolla Institute for Immunology, La Jolla, CA, USA
Monalisa Mondal
La Jolla Institute for Immunology, La Jolla, CA, USA
Matthew Ellis
NIHR and CRUK Southampton Experimental Cancer Medicine Center, Faculty of Medicine, University of Southampton, Southampton, UK; NIHR Southampton Biomedical Research Center, Faculty of Medicine, University of Southampton, Southampton, UK
Gareth J. Thomas
NIHR and CRUK Southampton Experimental Cancer Medicine Center, Faculty of Medicine, University of Southampton, Southampton, UK; NIHR Southampton Biomedical Research Center, Faculty of Medicine, University of Southampton, Southampton, UK
Vivek Chandra
La Jolla Institute for Immunology, La Jolla, CA, USA
Christian H. Ottensmeier
La Jolla Institute for Immunology, La Jolla, CA, USA; Department of Molecular and Clinical Cancer Medicine and NIHR and CRUK Liverpool Experimental Cancer Medicine Center, University of Liverpool, Liverpool, UK
Pandurangan Vijayanand
La Jolla Institute for Immunology, La Jolla, CA, USA; University of California San Diego, La Jolla, CA, USA; Department of Molecular and Clinical Cancer Medicine and NIHR and CRUK Liverpool Experimental Cancer Medicine Center, University of Liverpool, Liverpool, UK; Corresponding author
Summary: 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.
