IL-27 elicits a cytotoxic CD8+ T cell program to enforce tumour control

Béatrice Bréart, Katherine Williams, Stellanie Krimm, Tiffany Wong, Brandon D. Kayser, Lifen Wang, Eric Cheng, Mayra Cruz Tleugabulova, Romain Bouziat, Tianshi Lu, Kobe Yuen, Natalie S. Firmino, Daniel D. Bravo, Juliette Roels, Atish Bhakta, Jack Bevers, Isabelle Lehoux, Alan Gutierrez, Yajun Chestnut, Joanna E. Klementowicz, Teresita L. Arenzana, Ilseyar Akhmetzyanova, Elizabeth Dixon, Min Chen, Kazi Tasneem, Rajbharan Yadav, Hartmut Koeppen, Soyoung A. Oh, Lélia Delamarre, Haochu Huang, Shion A. Lim, Gerald Nakamura, Jianyong Wang, Chan Gao, Racquel Corpuz, Sören Müller () and Nathaniel R. West ()
Additional contact information
Béatrice Bréart: Genentech
Katherine Williams: Genentech
Stellanie Krimm: Genentech
Tiffany Wong: Genentech
Brandon D. Kayser: Genentech
Lifen Wang: Genentech
Eric Cheng: Genentech
Mayra Cruz Tleugabulova: Genentech
Romain Bouziat: Genentech
Tianshi Lu: Genentech
Kobe Yuen: Genentech
Natalie S. Firmino: Genentech
Daniel D. Bravo: Genentech
Juliette Roels: Genentech
Atish Bhakta: Genentech
Jack Bevers: Genentech
Isabelle Lehoux: Genentech
Alan Gutierrez: Genentech
Yajun Chestnut: Genentech
Joanna E. Klementowicz: Genentech
Teresita L. Arenzana: Genentech
Ilseyar Akhmetzyanova: Genentech
Elizabeth Dixon: Genentech
Min Chen: Genentech
Kazi Tasneem: Genentech
Rajbharan Yadav: Genentech
Hartmut Koeppen: Genentech
Soyoung A. Oh: Genentech
Lélia Delamarre: Genentech
Haochu Huang: Genentech
Shion A. Lim: Genentech
Gerald Nakamura: Genentech
Jianyong Wang: Genentech
Chan Gao: Genentech
Racquel Corpuz: Genentech
Sören Müller: Genentech
Nathaniel R. West: Genentech

Nature, 2025, vol. 639, issue 8055, 746-753

Abstract: Abstract Although cytotoxic CD8+ T lymphocytes (CTLs) are essential for anti-tumour immunity, they are frequently dysfunctional in tumours1. Cytokines that sustain CTL activity are attractive for cancer immunotherapy, but avoiding inflammatory toxicity remains a challenge for their clinical use2. Here we show that expression of a CTL signature is strongly associated with IL27 expression in human and mouse tumours. In mice, IL-27 acts directly on tumour-specific CTLs to promote their persistence and effector function in the tumour microenvironment. Moreover, treatment with inducible IL-27 overexpression or a half-life-extended IL-27 protein in vivo is well tolerated, induces regression of established tumours, drives an enhanced cytotoxic program in anti-tumour CTLs and synergizes with PD-L1 blockade. In patients with cancer who were treated with anti-PD-1/PD-L1 therapy, high expression of IL-27 correlates with a favourable clinical response, and IL-27 supports human CTL function during chronic antigen stimulation ex vivo. Our data demonstrate that endogenous IL-27 is essential for anti-tumour immunity and that IL-27 receptor agonism can safely improve anti-tumour T cell responses alone or in combination with PD-L1 blockade.

Date: 2025
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DOI: 10.1038/s41586-024-08510-w

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