Abstract
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.
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Data availability
The main data supporting the results of this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during this study are too large to be publicly shared, but they are available for research purposes from the corresponding author upon reasonable request. They also contain personal and patient data and are available for research purposes pending completion of adequate paper work ensuring personal data protection and ethical approval. RNA-sequencing data in this study have been published previously and are accessible through the NCBI Gene Expression Omnibus (accession codes GSE84133 and GSE122960), NCBI BioProject database (accession code PRJEB31843), Genome Sequence Archive (accession number CRA001160) and Synapse (https://www.synapse.org/#!Synapse:syn21041850/files/).
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Acknowledgements
This study was supported by the Wilhelm Sander-Stiftung (grant number 2014.018.1 to S.E. and S. Kobold), international doctoral program ‘i-Target: immunotargeting of cancer’ (funded by the Elite Network of Bavaria; to S. Kobold and S.E.), Melanoma Research Alliance (grant number N269626 to S.E. and grant number 409510 to S. Kobold), Marie Sklodowska-Curie Training Network for the Immunotherapy of Cancer (IMMUTRAIN) (funded by the Horizon 2020 programme of the European Union; to S.E. and S. Kobold), Marie Sklodowska-Curie Training Network for Optimizing Adoptive T Cell Therapy of Cancer (funded by the Horizon 2020 programme of the European Union; grant 955575 to S. Kobold), Else Kröner-Fresenius-Stiftung (to S. Kobold), German Cancer Aid (to S. Kobold), Ernst Jung Stiftung (to S. Kobold), Institutional Strategy LMUexcellent of LMU Munich (within the framework of the German Excellence Initiative; to S.E. and S. Kobold), Bundesministerium für Bildung und Forschung (to S.E. and S. Kobold), European Research Council (Starting Grant 756017 to S. Kobold), Deutsche Forschungsgemeinschaft (DFG; to S. Kobold), Fritz-Bender Foundation (to S. Kobold), José Carreras Foundation (to S. Kobold) and Hector Foundation (to S. Kobold). R.T.A.M. is supported by the DFG (INST409/97-1 FUGG), SFB1123/Z1 and ERA-CVD (AtheroInside). Z.D. was supported by an AGA-Moti L. & Kamla Rustgi International Travel Award. M. Reichert was supported by German Cancer Aid (Max Eder Program; Deutsche Krebshilfe 111273) and the DFG (SFB1321 (Modeling and Targeting Pancreatic Cancer) and RE 3723/4-1). E.D. was supported by a grant from INSERM (HTE: chemotaxis in cancer). M.T. is funded by the Volkswagen Foundation (project OntoTime). C.M. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement number 866411). M. Schnurr was supported by the DFG (SFB1321 (Modeling and Targeting Pancreatic Cancer); project number 329628492). We acknowledge the iFlow Core Facility of the University Hospital of Munich for assistance with the generation of flow cytometry data. Image processing using the Imaris 7.6.5 software was performed at the Core Facility for Bioimaging of the Biomedical Center of the Ludwig-Maximilians-Universität München.
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S.L., V.B., S.S., J.O., B.L.C., Z.D., F.R., K.D., J.L., C.H.K., C. Heise, M.K., B.M.L., S.G., M. Rapp, A.N., A.G., S. Kruger, N.T., P.M., C. Hoerth, M.-R.B., D.D., A.O., R.G., M. Seifert, S.J., Ö.U., L.V., M.T., T.T., T.H., T.B., D.H., R.T.A.M., K.-P.J., M.J., D.L., S. Ruehland, M.D.P., J.N.P., M.T., S.O., C.M., E.T., E.D., M.H., A.R., S. Rothenfusser, P.D., L.M.K. and M. Schnurr performed or assisted with the experiments, analysed the data and supported the project. S. Kobold and S.E. supervised the project and acquired the funding. S. Kobold, S.L., V.B., S.S., J.O., B.L.C., M. Subklewe, A.S.L., N.H., M. Reichert and T.R.M. designed the experiments. S. Kobold and S.L. wrote the manuscript. All authors critically read and approved the final manuscript.
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Parts of this work have been performed for the doctoral theses of S.L., V.B., S.S., K.D. and J.L. at the Ludwig-Maximilians-Universität München. M. Rapp, S.G., S.E. and S. Kobold are inventors on a patent application related to this work (PCT/EP2016/074644), filed by the Ludwig-Maximilians-Universität München. S.E. and S. Kobold received research support from TCR2 Therapeutics and Arcus Biosciences for work on T cell therapies unrelated to the present manuscript. The remaining authors declare no competing interests.
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Lesch, S., Blumenberg, V., Stoiber, S. et al. T cells armed with C-X-C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours. Nat Biomed Eng 5, 1246–1260 (2021). https://doi.org/10.1038/s41551-021-00737-6
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DOI: https://doi.org/10.1038/s41551-021-00737-6
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