Taxanes trigger cancer cell killing in vivo by inducing non-canonical T cell cytotoxicity

  • Cancer Cell. 2023 Jun 12;41(6):1170-1185.e12. doi: 10.1016/j.ccell.2023.05.009.
Claire Vennin  1 ,  Chiara M Cattaneo  2 ,  Leontien Bosch  3 ,  Serena Vegna  4 ,  Xuhui Ma  2 ,  Hugo G J Damstra  5 ,  Moreno Martinovic  6 ,  Efi Tsouri  4 ,  Mila Ilic  7 ,  Leyla Azarang  8 ,  Jan R T van Weering  9 ,  Emilia Pulver  1 ,  Amber L Zeeman  10 ,  Tim Schelfhorst  1 ,  Jeroen O Lohuis  1 ,  Anne C Rios  11 ,  Johanna F Dekkers  11 ,  Leila Akkari  4 ,  Renee Menezes  8 ,  Rene Medema  7 ,  Serena R Baglio  12 ,  Anna Akhmanova  5 ,  Sabine C Linn  13 ,  Simone Lemeer  14 ,  Dirk M Pegtel  3 ,  Emile E Voest  2 ,  Jacco van Rheenen  15
Affiliations
  • 1. Division of Molecular Pathology, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066CX Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands.
  • 2. Oncode Institute, Amsterdam, the Netherlands; Department of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066CX Amsterdam, the Netherlands.
  • 3. Department of Pathology, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081HV Amsterdam, the Netherlands.
  • 4. Oncode Institute, Amsterdam, the Netherlands; Division of Tumor Biology and Immunology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands.
  • 5. Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, 3584CT Utrecht, the Netherlands.
  • 6. Division of Gene Regulation, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066CX Amsterdam, the Netherlands.
  • 7. Oncode Institute, Amsterdam, the Netherlands; Division of Cell Biology, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066CX Amsterdam, the Netherlands.
  • 8. Biostatistics Centre & Department of Psychosocial Research and Epidemiology, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands.
  • 9. Department of Human Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam UMC, 1105AZ Amsterdam, the Netherlands.
  • 10. Oncode Institute, Amsterdam, the Netherlands; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre (UMC), 3584CT Utrecht, the Netherlands; Princess Maxima Center for Pediatric Oncology, 3584CT Utrecht, the Netherlands.
  • 11. Oncode Institute, Amsterdam, the Netherlands; Princess Maxima Center for Pediatric Oncology, 3584CT Utrecht, the Netherlands.
  • 12. Department of Pathology, Cancer Center Amsterdam, Amsterdam University Medical Center, Amsterdam, the Netherlands.
  • 13. Divisions of Molecular Pathology and of Medical Oncology, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Department of Pathology, University Medical Center, 1081HV Utrecht, the Netherlands.
  • 14. Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584CT Utrecht, the Netherlands; Netherlands Proteomics Center, 3584CT Utrecht, the Netherlands.
  • 15. Division of Molecular Pathology, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066CX Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands. Electronic address: [email protected].
PMID: 37311414 DOI: 10.1016/j.ccell.2023.05.009
Abstract

Although treatment with taxanes does not always lead to clinical benefit, all patients are at risk of their detrimental side effects such as peripheral neuropathy. Understanding the in vivo mode of action of taxanes can help design improved treatment regimens. Here, we demonstrate that in vivo, taxanes directly trigger T cells to selectively kill Cancer cells in a non-canonical, T cell receptor-independent manner. Mechanistically, taxanes induce T cells to release cytotoxic extracellular vesicles, which lead to Apoptosis specifically in tumor cells while leaving healthy epithelial cells intact. We exploit these findings to develop an effective therapeutic approach, based on transfer of T cells pre-treated with taxanes ex vivo, thereby avoiding toxicity of systemic treatment. Our study reveals a different in vivo mode of action of one of the most commonly used chemotherapies, and opens avenues to harness T cell-dependent anti-tumor effects of taxanes while avoiding systemic toxicity.

Keywords
T cell therapy; T cells; extracellular vesicles; in vivo mode of action; taxanes.
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