IL-27 neutralization to modulate the tumor microenvironment and increase immune checkpoint immunotherapy efficacy

Tumor-associated macrophages (TAMs) accumulate in most solid tumors, where they secrete inflammatory cytokines and growth factors that promote tumor progression, immune evasion, and angiogenesis. TAMs have recently emerged as therapeutic targets for reactivating antitumor immunity and restraining tumor progression. In this study, we investigated whether IL-27 neutralization could modulate macrophage polarization and thereby alter the tumor immune microenvironment. The effects of IL-27 neutralization were examined using complementary in vitro and in vivo approaches. In vitro, human macrophages were analyzed by flow cytometry, qRT-PCR, ELISA, and Western blot to assess changes in their immunoregulatory profile. In vivo, the MC38 murine colon adenocarcinoma model was used to evaluate the impact of IL-27 blockade on the tumor immune microenvironment. Our findings highlight a key role for IL-27 in promoting the immunosuppressive phenotype of human macrophages. Mechanistically, IL-27 neutralization diminished macrophage-mediated suppression by reducing cytokine production and the expression of immunoinhibitory surface molecules. These modifications led to a reduction in the ability of macrophages to inhibit the function of CD4{square} and CD8{square} T cells. Furthermore, in vivo neutralization of IL-27 attenuated MC38 tumor growth and enhanced the efficacy of immune checkpoint therapy. Collectively, targeting IL-27 promoted macrophage repolarization and enhanced CD4{square} and CD8{square} T cell responses. These findings suggest that IL-27 neutralization is a promising therapeutic strategy to reprogram macrophages in the tumor microenvironment (TME) and improve the clinical efficacy of cancer immunotherapy.