Abstract A059: IL-27 elicits a cytotoxic CD8+ T cell program to enforce tumour control

Abstract Cytotoxic CD8+ T lymphocytes (CTL) are essential for anti-tumour immunity but are frequently dysfunctional in established tumours. Cytokines that sustain CTL activity are attractive for cancer immunotherapy, but avoiding systemic inflammatory toxicity remains a challenge for their clinical use. Here, we show that expression of a CTL signature is strongly associated with IL-27 expression in human and murine tumours. In mice, IL-27 acts directly on tumour-specific CTL to promote their persistence and effector function in the tumour microenvironment (TME). 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 CTL, and synergizes with PD-L1 blockade. In cancer patients treated with anti-PD-1/PD-L1[bb1] therapy, high expression of IL-27 correlates with improved clinical response, and IL-27 supports human CTL function during chronic antigen stimulation. 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. Citation Format: Beatrice Breart, Nathaniel West. IL-27 elicits a cytotoxic CD8+ T cell program to enforce tumour control [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A059.