IL-27 neutralization promotes pro-inflammatory macrophage polarization and improve response to immune checkpoint blockade

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Abstract In this study, we investigated the role of interleukin-27 (IL-27) as a regulator of the tumor immune microenvironment (TME) and its impact on the CD39/adenosine metabolic axis. The effects of IL-27 neutralization were evaluated using both in vivo MC38 murine colon adenocarcinoma mode and in vitro human macrophage models. In vivo, we analyzed how IL-27 blockade affects tumor growth and the phenotype of infiltrating immune cells, particularly regarding their CD39 expression. In vitro, we focused on the impact of IL-27 during human macrophage differentiation using flow cytometry, metabolic analysis, and functional assays. Our findings demonstrate that within tumor IL-27 is a major driver of the immunosuppressive phenotype in both murine and human immune cells. Mechanistically, IL-27 induces high levels of the ectonucleotidase CD39, promoting an adenosine-mediated suppressive environment. In vivo, IL-27 blockade led to a broad downregulation of CD39 on both myeloid cells and exhausted T cells. This remodeling of the TME significantly attenuated tumor growth and enhanced the efficacy of anti-PD-L1 checkpoint therapy. We confirm that neutralizing IL-27 prevents the acquisition of immunoregulatory markers in human macrophages and induces significant metabolic reprogramming. Collectively, our results highlight the IL-27/CD39 axis as a key mechanism of immune evasion. We suggest that targeting IL-27 is a promising strategy to reprogram the metabolic and cellular state of the tumor microenvironment, improving the effectiveness of cancer immunotherapy.

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