CTLs play a key role in fighting cancer cells, but within the tumor microenvironment, they quickly become exhausted and lose effectiveness. Immunotherapy targeting CTLA-4, PD-1, and PD-L1 helps activate T cells in some patients but is often ineffective. Therefore, new strategies are needed to enhance T cell anti-tumor responses.
One potential approach is cytokine therapy, which activates immune cells. However, well-studied cytokines such as IL-2, IL-12, and type I interferons (IFN) often cause side effects and are rapidly eliminated from the body, limiting their clinical use.
Scientists from Genentech, a biotechnology company specializing in drug discovery and development for life-threatening diseases, proposed IL-27 as a candidate for cancer immunotherapy.
IL-27 facilitates CTL infiltration into tumors. In mice, IL-27 signaling in CTLs is required for protective anti-tumor immunity. Stimulation of the IL-27 receptor enhances CTL responses and tumor control without causing significant toxicity. Conversely, in mice lacking IL-27 signaling, tumor growth accelerates. However, previous concerns suggested IL-27 might induce CTL dysfunction by upregulating co-inhibitory PD-1 receptors. This study refines our understanding of IL-27’s role in tumor-specific CTLs.
IL-27 Enhances Key T Cell Functions
IL-27 supports T cell activity, cytokine signaling, and antigen presentation—key processes for immune attack on tumors.
To investigate IL-27’s effects on CTLs within tumors, researchers used a mouse model of colorectal carcinoma. They found that IL-27 is produced by myeloid cells, and its receptors are predominantly expressed in T cells and NK cells.
Experiments revealed that tumors grew faster without IL-27 due to genetic mutation or neutralizing antibodies. While CTL frequency remained stable in draining lymph nodes, it significantly decreased within tumors. IL-27 deficiency was associated with a reduced CD8/Treg ratio in tumors. Blocking IL-27 or deleting its receptor reduced the number of CTLs with cytotoxic anti-tumor activity capable of killing cancer cells. Additionally, CTL proliferation and the production of effector molecules such as granzyme B declined. IL-27 blockade disrupted the differentiation of TH1 and Treg1 cells and impaired CD4+ T cell function within tumors.
IL-27 from Dendritic Cells Drives Antitumor CTL Activity
IL-27 produced by dendritic cells plays a crucial role in activating anti-tumor CTLs.
Researchers identified which cells produce IL-27 necessary for CTL activation. When IL-27 was removed from phagocytes, no significant impact on immune response was observed. However, deleting IL-27 from dendritic cells led to a sharp decline in anti-tumor immunity.
For CTLs to maintain sustained anti-tumor function, direct IL-27 stimulation is required. CTLs lacking the IL-27 receptor exhibited reduced tumor infiltration and lost their ability to combat cancer effectively.
IL-27 Receptor Stimulation Enhances Immunity Against Resistant Tumors
Stimulating the IL-27 receptor can boost anti-tumor immunity and even lead to tumor rejection.
Using tail-vein injection, researchers delivered DNA encoding IL-27 to the liver of mice with colorectal carcinoma, leading to elevated IL-27 levels in the bloodstream for a week. This stimulation of the IL-27 receptor resulted in complete tumor rejection in most mice without causing significant toxicity.
For comparison, overexpression of other cytokines from the same family (IL-6, IL-12, IL-23) induced inflammation and weight loss. IL-27 promoted CTL proliferation and cytotoxic activity while preventing exhaustion. Unlike other cytokines, IL-27 did not increase suppressive Treg cell populations. As a result, the CD8/Treg ratio increased, strengthening the immune response against tumors.
Additionally, IL-27 enhanced CTL production of granzyme A and B, enzymes that destroy cancer cells. Similar results were observed in human cytotoxic T lymphocytes, where IL-27 improved CTL recruitment, increased granzyme B production, and prevented exhaustion. IL-27 also contributed to cytotoxic and effector memory formation.
Researchers tested whether this strategy worked against other cancers, such as breast cancer and melanoma, which are resistant to standard immunotherapy. IL-27 receptor stimulation strengthened the immune response in these cases, particularly when combined with immune checkpoint blockade (PD-L1). Combination therapy slowed tumor growth or led to tumor regression.
IL-27-Fc Protein Induces Tumor Regression
Scientists engineered an IL-27-Fc protein with a serum half-life nearly 200 times longer than that of IL-27—lasting 2.9 days.
Like native IL-27, IL-27-Fc effectively activated STAT1 and STAT3 and induced dose-dependent tumor regression. IL-27-Fc increased CTL activity, improved the CTL/Treg ratio, and boosted granzyme B production, promoting tumor elimination. However, in mice lacking the IL-27 receptor, IL-27-Fc treatment had no significant effect.
IL-27 Expression Predicts Cancer Immunotherapy Success
Researchers analyzed RNA sequencing data from tumor samples of patients with metastatic urothelial bladder carcinoma and non-small cell lung cancer treated with atezolizumab (anti-PD-L1) or chemotherapy.
Patients with high IL-27 levels in tumors showed improved overall survival. This effect was observed only in patients receiving anti-PD-L1 therapy. High IL-27 levels correlated with CTL activity and the activation of genes associated with macrophages and dendritic cells.
In a separate study on melanoma patients, increased IL-27 expression during nivolumab (anti-PD-1) treatment was linked to a favorable clinical response. IL-27 expression significantly rose during therapy only in patients who responded to treatment.
Conclusion
IL-27 enhances T cell-mediated tumor control by improving CTL infiltration and cytotoxic function. Blocking IL-27 signaling weakens anti-tumor T cell responses, whereas increasing IL-27 levels strengthens them.
IL-27 reduces gene activity associated with T cell exhaustion and supports their cytotoxic function. IL-27 expression is associated with favorable clinical responses in cancer therapy, making it a promising tool for enhancing the effectiveness of cancer immunotherapy.
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Reference
IL-27 elicits a cytotoxic CD8+ T cell program to enforce tumour control
