Intratumoral expression of JAML on NK cells is controlled by tumor microenvironment and MHC class I interaction

Labuz, D.; Angenendt, S.; Marek, N.; Bremser, J.; Braddish, D. M.; Nyman, L.; Fischbach, J.; Keim, L.; Hyland, A.; Bento, C.; Michie, R.; Lane, R. M.; Passacatini, C.; Pei, S.; Pan, Y.; Karlsson, M. C. I.; Pumpe, A.; Oppelt, A.-S.; Wilhelm, M.; Tibbitt, C.; Chan, S.; Ribacke, U.; Saldan, A.; Kärre, K.; Johansson, M. H.; Wagner, A. K.; Coquet, J.; Chambers, B. J.

doi:10.64898/2026.04.15.718645

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bioRxiv · 10.64898/2026.04.15.718645

Intratumoral expression of JAML on NK cells is controlled by tumor microenvironment and MHC class I interaction

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Abstract

Junctional adhesion molecule-like (JAML) is an adhesion molecule known to promote T cell activation and T cell-mediated tumor rejection. In the current study, we show that JAML expression is enriched on mouse intratumoral NK cells compared with splenic NK cells. JAML+ NK cells were associated with tissue residency and co-expressed the immune checkpoints PD-1 and LAG3. JAML expression could be induced on splenic NK cells by IL-2 and further enhanced by IL-21. JAML levels were inversely correlated with inhibitory signaling, as NK cells expressing self-recognizing Ly49 receptors had reduced JAML expression, suggesting regulation of JAML expression by MHC class I molecules. Interaction with the JAML ligand CXADR also reduced JAML surface expression, indicating that tumor-mediated membrane stripping may represent a mechanism of immunoediting. Although JAML RNA transcripts were detectable in human NK cells, JAML protein was found only intracellularly. Together, these findings identify the JAML-CXADR interaction as a potential regulatory pathway in NK cell-mediated killing of tumors.

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Labuz, D., Angenendt, S., Marek, N., Bremser, J., Braddish, D. M., Nyman, L., Fischbach, J., Keim, L., Hyland, A., Bento, C., Michie, R., Lane, R. M., Passacatini, C., Pei, S., Pan, Y., Karlsson, M. C. I., Pumpe, A., Oppelt, A.-S., Wilhelm, M., Tibbitt, C., Chan, S., Ribacke, U., Saldan, A., Kärre, K., Johansson, M. H., Wagner, A. K., Coquet, J., Chambers, B. J.. 2026-04-20. Intratumoral expression of JAML on NK cells is controlled by tumor microenvironment and MHC class I interaction. https://doi.org/10.64898/2026.04.15.718645

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