T cells armed with C-X-C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours

Lesch, S., Blumenberg, V., Stoiber, S., Gottschlich, A., Ogonek, J., Cadilha, B. L., Dantes, Z., Rataj, F., Dorman, K., Lutz, J., Karches, C. H., Heise, C., Kurzay, M., Larimer, B. M., Grassmann, S., Rapp, M., Nottebrock, A., Kruger, S., Tokarew, N., Metzger, P., Hoerth, C., Benmebarek, M. R., Dhoqina, D., Grunmeier, R., Seifert, M., Oener, A., Umut, O., Joaquina, S., Vimeux, L., Tran, T., Hank, T., Baba, T., Huynh, D., Megens, R. T. A., Janssen, K. P., Jastroch, M., Lamp, D., Ruehland, S., Di Pilato, M., Pruessmann, J. N., Thomas, M., Marr, C., Ormanns, S., Reischer, A., Hristov, M., Tartour, E., Donnadieu, E., Rothenfusser, S., Duewell, P., Konig, L. M., Schnurr, M., Subklewe, M., Liss, A. S., Halama, N., Reichert, M., Mempel, T. R., Endres, S., and Kobold, S. (2021). Nat Biomed Eng 5, 1246-1260. doi: 10.1038/s41551-021-00737-6


The efficacy of adoptive cell therapy for solid tumours is hampered by the poor accumulation of the transferred T cells in tumour tissue. Here, we show that forced expression of C-X-C chemokine receptor type 6 (whose ligand is highly expressed by human and murine pancreatic cancer cells and tumour-infiltrating immune cells) in antigen-specific T cells enhanced the recognition and lysis of pancreatic cancer cells and the efficacy of adoptive cell therapy for pancreatic cancer. In mice with subcutaneous pancreatic tumours treated with T cells with either a transgenic T-cell receptor or a murine chimeric antigen receptor targeting the tumour-associated antigen epithelial cell adhesion molecule, and in mice with orthotopic pancreatic tumours or patient-derived xenografts treated with T cells expressing a chimeric antigen receptor targeting mesothelin, the T cells exhibited enhanced intratumoral accumulation, exerted sustained anti-tumoral activity and prolonged animal survival only when co-expressing C-X-C chemokine receptor type 6. Arming tumour-specific T cells with tumour-specific chemokine receptors may represent a promising strategy for the realization of adoptive cell therapy for solid tumours.