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 journalArticleAcademicpeer-review

14 Citations (Web of Science)

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 languageEnglish
Pages (from-to)1246–1260
Number of pages21
JournalNature Biomedical Engineering
Volume5
Issue number11
DOIs
Publication statusPublished - Nov 2021

Keywords

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

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