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

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. [Display omitted] •T cells mediate taxane cytotoxicity in vivo•Taxanes trigger T cells to release cytotoxic extracellular vesicles•Taxanes increase TCR-independent and TCR-mediated T cell killing•T cells treated ex vivo with taxanes can eradicate tumors in vivo Discrepancies exist between the in vitro versus in vivo mode of action of taxanes. Vennin et al. uncover that taxanes directly trigger T cells to kill tumor cells by inducing a release of cytotoxic extracellular vesicles. This cytotoxic activity has strong therapeutic activity in organoids from patients with cancer and in tumor-bearing mice.