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

Claire Vennin; Chiara M Cattaneo; Leontien Bosch; Serena Vegna; Xuhui Ma; Hugo G J Damstra; Moreno Martinovic; Efi Tsouri; Mila Ilic; Leyla Azarang; Jan R T van Weering; Emilia Pulver; Amber L Zeeman; Tim Schelfhorst; Jeroen O Lohuis; Anne C Rios; Johanna F Dekkers; Leila Akkari; Renee Menezes; Rene Medema; Serena R Baglio; Anna Akhmanova; Sabine C Linn; Simone Lemeer; Dirk M Pegtel; Emile E Voest; Jacco van Rheenen

doi:10.1016/j.ccell.2023.05.009

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

Claire Vennin, Chiara M Cattaneo, Leontien Bosch, Serena Vegna, Xuhui Ma, Hugo G J Damstra, Moreno Martinovic, Efi Tsouri, Mila Ilic, Leyla Azarang, Jan R T van Weering, Emilia Pulver, Amber L Zeeman, Tim Schelfhorst, Jeroen O Lohuis, Anne C Rios, Johanna F Dekkers, Leila Akkari, Renee Menezes, Rene MedemaSerena R Baglio, Anna Akhmanova, Sabine C Linn, Simone Lemeer, Dirk M Pegtel, Emile E Voest, Jacco van Rheenen^*

^*Corresponding author for this work

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

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.

Original language	English
Article number	e12
Pages (from-to)	1170-1185.e12
Number of pages	16
Journal	Cancer Cell
Volume	41
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2023.05.009
Publication status	Published - 12 Jun 2023

Bibliographical note

Funding

Funding: This work was supported by the Netherlands Organization of Scientific Research NWO (Vici grant 09150182110004 , CancerGenomics.nl , and the Josef Steiner Cancer Research Foundation (JvR). CV is funded by a fellowship from the Human Frontiers in Science Program . The funders had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the paper; or in the decision to submit the paper for publication.

Funders	Funder number
Netherlands Organization of Scientific Research NWO	09150182110004
Dr. Josef Steiner Krebsstiftung

Keywords

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

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Cite this

Vennin, C., Cattaneo, C. M., Bosch, L., Vegna, S., Ma, X., Damstra, H. G. J., Martinovic, M., Tsouri, E., Ilic, M., Azarang, L., van Weering, J. R. T., Pulver, E., Zeeman, A. L., Schelfhorst, T., Lohuis, J. O., Rios, A. C., Dekkers, J. F., Akkari, L., Menezes, R., ... van Rheenen, J. (2023). Taxanes trigger cancer cell killing in vivo by inducing non-canonical T cell cytotoxicity. Cancer Cell, 41(6), 1170-1185.e12. Article e12. https://doi.org/10.1016/j.ccell.2023.05.009

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title = "Taxanes trigger cancer cell killing in vivo by inducing non-canonical T cell cytotoxicity",

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.",

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year = "2023",

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Vennin, C, Cattaneo, CM, Bosch, L, Vegna, S, Ma, X, Damstra, HGJ, Martinovic, M, Tsouri, E, Ilic, M, Azarang, L, van Weering, JRT, Pulver, E, Zeeman, AL, Schelfhorst, T, Lohuis, JO, Rios, AC, Dekkers, JF, Akkari, L, Menezes, R, Medema, R, Baglio, SR, Akhmanova, A, Linn, SC, Lemeer, S, Pegtel, DM, Voest, EE & van Rheenen, J 2023, 'Taxanes trigger cancer cell killing in vivo by inducing non-canonical T cell cytotoxicity', Cancer Cell, vol. 41, no. 6, e12, pp. 1170-1185.e12. https://doi.org/10.1016/j.ccell.2023.05.009

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T1 - Taxanes trigger cancer cell killing in vivo by inducing non-canonical T cell cytotoxicity

AU - Vennin, Claire

AU - Cattaneo, Chiara M

AU - Bosch, Leontien

AU - Vegna, Serena

AU - Ma, Xuhui

AU - Damstra, Hugo G J

AU - Martinovic, Moreno

AU - Tsouri, Efi

AU - Ilic, Mila

AU - Azarang, Leyla

AU - van Weering, Jan R T

AU - Pulver, Emilia

AU - Zeeman, Amber L

AU - Schelfhorst, Tim

AU - Lohuis, Jeroen O

AU - Rios, Anne C

AU - Dekkers, Johanna F

AU - Akkari, Leila

AU - Menezes, Renee

AU - Medema, Rene

AU - Baglio, Serena R

AU - Akhmanova, Anna

AU - Linn, Sabine C

AU - Lemeer, Simone

AU - Pegtel, Dirk M

AU - Voest, Emile E

AU - van Rheenen, Jacco

PY - 2023/6/12

Y1 - 2023/6/12

N2 - 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.

AB - 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.

KW - T cell therapy

KW - T cells

KW - extracellular vesicles

KW - in vivo mode of action

KW - taxanes

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DO - 10.1016/j.ccell.2023.05.009

M3 - Article

C2 - 37311414

SN - 1535-6108

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SP - 1170-1185.e12

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JF - Cancer Cell

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