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 Grunmeier; Matthias Seifert; Arman Oener; Oyku 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. Konig; 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 Grunmeier, Matthias Seifert, Arman Oener, Oyku 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. Konig, Max Schnurr, Marion Subklewe, Andrew S. Liss, Niels Halama, Maximilian Reichert, Thorsten R. Mempel, Stefan Endres, Sebastian Kobold^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Forced expression of C-X-C chemokine receptor type 6 in antigen-specific T cells enhanced the recognition and lysis of pancreatic cancer cells and the efficacy of adoptive cell therapy for pancreatic cancer.

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
Pages (from-to)	1246–1260
Number of pages	21
Journal	Nature Biomedical Engineering
Volume	5
Issue number	11
DOIs	https://doi.org/10.1038/s41551-021-00737-6
Publication status	Published - Nov 2021

Keywords

CHIMERIC ANTIGEN RECEPTOR
CXC CHEMOKINE
INFILTRATING LYMPHOCYTES
IMMUNE CELLS
IMMUNOTHERAPY
CANCER
RECRUITMENT
EXPRESSION
LOCALIZATION
TRANSDUCTION

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10.1038/s41551-021-00737-6

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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, 5(11), 1246–1260. https://doi.org/10.1038/s41551-021-00737-6

@article{fcd05c0572e945728a08a751178744fb,

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

abstract = "Forced expression of C-X-C chemokine receptor type 6 in antigen-specific T cells enhanced the recognition and lysis of pancreatic cancer cells and the efficacy of adoptive cell therapy for pancreatic cancer.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.",

keywords = "CHIMERIC ANTIGEN RECEPTOR, CXC CHEMOKINE, INFILTRATING LYMPHOCYTES, IMMUNE CELLS, IMMUNOTHERAPY, CANCER, RECRUITMENT, EXPRESSION, LOCALIZATION, TRANSDUCTION",

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 Mohamed-Reda Benmebarek and Dario Dhoqina and Ruth Grunmeier and Matthias Seifert and Arman Oener and Oyku 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 Klaus-Peter Janssen 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 Konig, {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 = "Funding Information: This study was supported by the Wilhelm Sander-Stiftung (grant number 2014.018.1 to S.E. and S. Kobold), international doctoral program {\textquoteleft}i-Target: immunotargeting of cancer{\textquoteright} (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 Kr{\"o}ner-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 f{\"u}r 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), Jos{\'e} 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{\textquoteright}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-Universit{\"a}t M{\"u}nchen. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2021",

month = nov,

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

language = "English",

volume = "5",

pages = "1246–1260",

journal = "Nature Biomedical Engineering",

issn = "2157-846X",

publisher = "Nature Publishing Group",

number = "11",

}

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, 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, RTA, Janssen, K-P, 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, Konig, 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, vol. 5, no. 11, pp. 1246–1260. 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 - Grunmeier, Ruth

AU - Seifert, Matthias

AU - Oener, Arman

AU - Umut, Oyku

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 - Konig, 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

N1 - Funding Information: 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. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2021/11

Y1 - 2021/11

N2 - Forced expression of C-X-C chemokine receptor type 6 in antigen-specific T cells enhanced the recognition and lysis of pancreatic cancer cells and the efficacy of adoptive cell therapy for pancreatic cancer.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 - Forced expression of C-X-C chemokine receptor type 6 in antigen-specific T cells enhanced the recognition and lysis of pancreatic cancer cells and the efficacy of adoptive cell therapy for pancreatic cancer.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.

KW - CHIMERIC ANTIGEN RECEPTOR

KW - CXC CHEMOKINE

KW - INFILTRATING LYMPHOCYTES

KW - IMMUNE CELLS

KW - IMMUNOTHERAPY

KW - CANCER

KW - RECRUITMENT

KW - EXPRESSION

KW - LOCALIZATION

KW - TRANSDUCTION

U2 - 10.1038/s41551-021-00737-6

DO - 10.1038/s41551-021-00737-6

M3 - Article

C2 - 34083764

SN - 2157-846X

VL - 5

SP - 1246

EP - 1260

JO - Nature Biomedical Engineering

JF - Nature Biomedical Engineering

IS - 11

ER -

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

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Keywords

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