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

Stefanie Lesch; Viktoria Blumenberg; Stefan Stoiber; Adrian Gottschlich; Justyna Ogonek; Bruno L. Cadilha; Zahra Dantes; Felicitas Rataj; Klara Dorman; Johannes Lutz; Clara H. Karches; Constanze Heise; Mathias Kurzay; Benjamin M. Larimer; Simon Grassmann; Moritz Rapp; Alessia Nottebrock; Stephan Kruger; Nicholas Tokarew; Philipp Metzger; Christine Hoerth; Mohamed Reda Benmebarek; Dario Dhoqina; Ruth Grünmeier; Matthias Seifert; Arman Oener; Öykü Umut; Sandy Joaquina; Lene Vimeux; Thi Tran; Thomas Hank; Taisuke Baba; Duc Huynh; Remco T.A. Megens; Klaus Peter Janssen; Martin Jastroch; Daniel Lamp; Svenja Ruehland; Mauro Di Pilato; Jasper N. Pruessmann; Moritz Thomas; Carsten Marr; Steffen Ormanns; Anna Reischer; Michael Hristov; Eric Tartour; Emmanuel Donnadieu; Simon Rothenfusser; Peter Duewell; Lars M. König; Max Schnurr; Marion Subklewe; Andrew S. Liss; Niels Halama; Maximilian Reichert; Thorsten R. Mempel; Stefan Endres; Sebastian Kobold

doi:10.1038/s41551-021-00737-6

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

Stefanie Lesch, Viktoria Blumenberg, Stefan Stoiber, Adrian Gottschlich, Justyna Ogonek, Bruno L. Cadilha, Zahra Dantes, Felicitas Rataj, Klara Dorman, Johannes Lutz, Clara H. Karches, Constanze Heise, Mathias Kurzay, Benjamin M. Larimer, Simon Grassmann, Moritz Rapp, Alessia Nottebrock, Stephan Kruger, Nicholas Tokarew, Philipp MetzgerChristine Hoerth, Mohamed Reda Benmebarek, Dario Dhoqina, Ruth Grünmeier, Matthias Seifert, Arman Oener, Öykü Umut, Sandy Joaquina, Lene Vimeux, Thi Tran, Thomas Hank, Taisuke Baba, Duc Huynh, Remco T.A. Megens, Klaus Peter Janssen, Martin Jastroch, Daniel Lamp, Svenja Ruehland, Mauro Di Pilato, Jasper N. Pruessmann, Moritz Thomas, Carsten Marr, Steffen Ormanns, Anna Reischer, Michael Hristov, Eric Tartour, Emmanuel Donnadieu, Simon Rothenfusser, Peter Duewell, Lars M. König, Max Schnurr, Marion Subklewe, Andrew S. Liss, Niels Halama, Maximilian Reichert, Thorsten R. Mempel, Stefan Endres, Sebastian Kobold^*

^*Corresponding author for this work

Clinic of Dermatology, Allergology and Venerology

153 Citations (Scopus)

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.

Original language	English
Journal	Nature Biomedical Engineering
DOIs	https://doi.org/10.1038/s41551-021-00737-6
Publication status	Published - 2021

Funding

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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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., ... Kobold, S. (2021). T cells armed with C-X-C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours. Nature Biomedical Engineering. https://doi.org/10.1038/s41551-021-00737-6

@article{0b993e03045245aaaa21dbf25999bc37,

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

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.",

author = "Stefanie Lesch and Viktoria Blumenberg and Stefan Stoiber and Adrian Gottschlich and Justyna Ogonek and Cadilha, \{Bruno L.\} and Zahra Dantes and Felicitas Rataj and Klara Dorman and Johannes Lutz and Karches, \{Clara H.\} and Constanze Heise and Mathias Kurzay and Larimer, \{Benjamin M.\} and Simon Grassmann and Moritz Rapp and Alessia Nottebrock and Stephan Kruger and Nicholas Tokarew and Philipp Metzger and Christine Hoerth and Benmebarek, \{Mohamed Reda\} and Dario Dhoqina and Ruth Gr{\"u}nmeier and Matthias Seifert and Arman Oener and {\"O}yk{\"u} Umut and Sandy Joaquina and Lene Vimeux and Thi Tran and Thomas Hank and Taisuke Baba and Duc Huynh and Megens, \{Remco T.A.\} and Janssen, \{Klaus Peter\} and Martin Jastroch and Daniel Lamp and Svenja Ruehland and \{Di Pilato\}, Mauro and Pruessmann, \{Jasper N.\} and Moritz Thomas and Carsten Marr and Steffen Ormanns and Anna Reischer and Michael Hristov and Eric Tartour and Emmanuel Donnadieu and Simon Rothenfusser and Peter Duewell and K{\"o}nig, \{Lars M.\} and Max Schnurr and Marion Subklewe and Liss, \{Andrew S.\} and Niels Halama and Maximilian Reichert and Mempel, \{Thorsten R.\} and Stefan Endres and Sebastian Kobold",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2021",

doi = "10.1038/s41551-021-00737-6",

language = "English",

journal = "Nature Biomedical Engineering",

issn = "2157-846X",

publisher = "Nature Research",

}

Lesch, S, Blumenberg, V, Stoiber, S, Gottschlich, A, Ogonek, J, Cadilha, BL, Dantes, Z, Rataj, F, Dorman, K, Lutz, J, Karches, CH, Heise, C, Kurzay, M, Larimer, BM, Grassmann, S, Rapp, M, Nottebrock, A, Kruger, S, Tokarew, N, Metzger, P, Hoerth, C, Benmebarek, MR, Dhoqina, D, Grünmeier, R, Seifert, M, Oener, A, Umut, Ö, Joaquina, S, Vimeux, L, Tran, T, Hank, T, Baba, T, Huynh, D, Megens, RTA, Janssen, KP, Jastroch, M, Lamp, D, Ruehland, S, Di Pilato, M, Pruessmann, JN, Thomas, M, Marr, C, Ormanns, S, Reischer, A, Hristov, M, Tartour, E, Donnadieu, E, Rothenfusser, S, Duewell, P, König, LM, Schnurr, M, Subklewe, M, Liss, AS, Halama, N, Reichert, M, Mempel, TR, Endres, S & Kobold, S 2021, 'T cells armed with C-X-C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours', Nature Biomedical Engineering. https://doi.org/10.1038/s41551-021-00737-6

TY - JOUR

T1 - T cells armed with C-X-C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours

AU - Lesch, Stefanie

AU - Blumenberg, Viktoria

AU - Stoiber, Stefan

AU - Gottschlich, Adrian

AU - Ogonek, Justyna

AU - Cadilha, Bruno L.

AU - Dantes, Zahra

AU - Rataj, Felicitas

AU - Dorman, Klara

AU - Lutz, Johannes

AU - Karches, Clara H.

AU - Heise, Constanze

AU - Kurzay, Mathias

AU - Larimer, Benjamin M.

AU - Grassmann, Simon

AU - Rapp, Moritz

AU - Nottebrock, Alessia

AU - Kruger, Stephan

AU - Tokarew, Nicholas

AU - Metzger, Philipp

AU - Hoerth, Christine

AU - Benmebarek, Mohamed Reda

AU - Dhoqina, Dario

AU - Grünmeier, Ruth

AU - Seifert, Matthias

AU - Oener, Arman

AU - Umut, Öykü

AU - Joaquina, Sandy

AU - Vimeux, Lene

AU - Tran, Thi

AU - Hank, Thomas

AU - Baba, Taisuke

AU - Huynh, Duc

AU - Megens, Remco T.A.

AU - Janssen, Klaus Peter

AU - Jastroch, Martin

AU - Lamp, Daniel

AU - Ruehland, Svenja

AU - Di Pilato, Mauro

AU - Pruessmann, Jasper N.

AU - Thomas, Moritz

AU - Marr, Carsten

AU - Ormanns, Steffen

AU - Reischer, Anna

AU - Hristov, Michael

AU - Tartour, Eric

AU - Donnadieu, Emmanuel

AU - Rothenfusser, Simon

AU - Duewell, Peter

AU - König, Lars M.

AU - Schnurr, Max

AU - Subklewe, Marion

AU - Liss, Andrew S.

AU - Halama, Niels

AU - Reichert, Maximilian

AU - Mempel, Thorsten R.

AU - Endres, Stefan

AU - Kobold, Sebastian

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85107273390

U2 - 10.1038/s41551-021-00737-6

DO - 10.1038/s41551-021-00737-6

M3 - Journal articles

AN - SCOPUS:85107273390

SN - 2157-846X

JO - Nature Biomedical Engineering

JF - Nature Biomedical Engineering

ER -

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

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