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

Area of Science:

• Immunology
• Cancer Biology
• Molecular Medicine

Background:

• Cytotoxic CD8+ T lymphocytes (CTLs) are crucial for anti-tumour immunity but often become dysfunctional within tumours.
• Cytokines that enhance CTL activity are promising for cancer immunotherapy, yet managing inflammatory toxicity is a clinical hurdle.

Purpose of the Study:

• To investigate the role of Interleukin-27 (IL-27) in anti-tumour immunity and its therapeutic potential in cancer immunotherapy.

Main Methods:

• Correlative analysis of IL-27 expression with CTL signatures in human and mouse tumours.
• In vivo studies using inducible IL-27 overexpression and IL-27 protein administration in mouse cancer models.
• Evaluation of IL-27's effect on human CTL function ex vivo and correlation with clinical responses in patients treated with anti-PD-1/PD-L1 therapy.

Main Results:

• IL-27 expression is strongly associated with CTL signatures in tumours.
• IL-27 directly enhances CTL persistence and effector function within the tumour microenvironment in mice.
• IL-27 therapy was well-tolerated, induced tumour regression, improved CTL cytotoxic programs, and synergized with PD-L1 blockade.
• High IL-27 expression correlated with favourable responses to anti-PD-1/PD-L1 therapy in cancer patients.

Conclusions:

• Endogenous IL-27 is vital for effective anti-tumour immunity.
• IL-27 receptor agonism offers a safe and effective strategy to enhance anti-tumour T cell responses, alone or combined with PD-L1 blockade.