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

Abstract

Objectives Tumor-associated macrophages (TAMs) accumulate in the majority of solid tumors, producing inflammatory cytokines and growth factors involved in tumor maintenance. They have recently emerged as targets for restoring an effective antitumor response and limiting tumor growth. In the present study, we investigated the potential of IL-27 neutralization to modify macrophage polarization and thus the tumor immune microenvironment. Methods and Analysis We monitored the effect of IL-27 neutralization on human macrophages. Flow cytometry, quantitative reverse transcription-PCR, ELISA and western blot were performed to validate, in vitro, the role of IL-27 on the acquisition of macrophage immunoregulatory functions. A murine Colon Adenocarcinoma model (MC38) was used to assess IL-27 neutralization in the microenvironment in vivo. Results In this study, we demonstrated the importance of IL-27 in the generation of human immunoregulatory macrophages. Mechanistically, IL-27 neutralization reduced the immunosuppressive properties of macrophages, such as cytokine secretion and membrane expression of immunosuppressive molecules. These modifications led to a reduction in the ability of macrophages to inhibit the function of CD4+ and CD8+ T cells. Furthermore, in vivo neutralization of IL-27 reduced MC38 tumor growth and could improve immune checkpoint inhibitor efficacy. Conclusions Collectively, we uncovered the role of IL-27 in the immunosuppressive tumor microenvironment (TME). We showed that IL-27 could be a target for macrophage repolarization and boosting of CD4+ and CD8+ T cell responses. IL-27 neutralization thus appears as a promising strategy to target macrophages in immunosuppressive TME and improve the clinical efficacy of immunotherapy protocols.