JAML-CAR – A Mechanism of T Cell Antitumor Immunity

Abstract The junctional adhesion molecule-like protein (JAML) is expressed by a variety of immune cell subsets and binds the Coxsackie and adenovirus receptor (CAR), an adhesion molecule expressed in epithelial tissues. Previous work from our lab demonstrated that JAML-CAR interactions are a unique costimulatory mechanism that controls activation of tissue-resident γδ T cells. High expression of JAML within tumors is associated with improved patient survival in a variety of epithelial cancers, yet the role of JAML-CAR interactions in antitumor immunity has not been characterized. Based on this evidence and the fact that CAR is expressed in epithelial tissues where many tumors arise, we hypothesized that JAML-CAR interactions are critical for antitumor immunity. Initial results utilizing the B16F10 melanoma model show that JAML−/− mice are more susceptible to tumor growth and have fewer γδ and CD8 T cells within tumors compared to WT mice. In WT mice, JAML is upregulated on γδ and CD8 T cells following activation, and a large fraction of γδ and CD8 tumor-infiltrating lymphocytes express JAML. Expression of CAR in mouse B16F10 melanoma is detectable within tumor margins but not within the tumor interior, and in human melanoma, CAR expression decreases with increased malignancy. This data suggests that tumors can downregulate CAR to escape immune responses. In support of this hypothesis, overexpression of CAR on B16F10 melanoma results in slower tumor formation and growth in WT mice but not RAG−/− or JAML−/− mice, which indicates that expression of CAR sensitives tumors to immune detection. These results show that JAML-CAR interactions are critical for T cell antitumor immunity and may be a novel therapeutic target to treat epithelial cancers.