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

• 成果类型: Article
• 署名作者: Breart, Beatrice; Williams, Katherine; Krimm, Stellanie; Wong, Tiffany; Kayser, Brandon D.; Wang, Lifen; Cheng, Eric; Tleugabulova, Mayra Cruz; Bouziat, Romain; Lu, Tianshi; Yuen, Kobe; Firmino, Natalie S.; Bravo, Daniel D.; Roels, Juliette; Bhakta, Atish; Bevers, Jack; Lehoux, Isabelle; Gutierrez, Alan; Chestnut, Yajun; Klementowicz, Joanna E.; Arenzana, Teresita L.; Akhmetzyanova, Ilseyar; Dixon, Elizabeth; Chen, Min; Tasneem, Kazi; Yadav, Rajbharan; Koeppen, Hartmut; Oh, Soyoung A.; Delamarre, Lelia; Huang, Haochu; Lim, Shion A.; Nakamura, Gerald; Wang, Jianyong; Gao, Chan; Corpuz, Racquel; Mueller, Soeren; West, Nathaniel R.
• 署名单位: Roche Holding; Roche Holding USA; Genentech
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3440
• DOI: 10.1038/s41586-024-08510-w
• 发表日期: 2025-03-20
• 关键词: gene-expression; cd8+t cells; open-label; cytokine; receptor; interleukin-27; atezolizumab; multicenter; antitumor; phase-3

摘要

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.