Interleukin 32 Promotes Foxp3(+) Treg Cell Development and CD8(+) T Cell Function in Human Esophageal Squamous Cell Carcinoma Microenvironment

Proinflammatory cytokine interleukin 32 (IL-32) is involved in infectious diseases and cancer, but what subtypes of immune cells express IL-32 and its roles in tumor microenvironment (TME) have not been well discussed. In this study, we applied bioinformatics to analyze single-cell RNA sequencing data about tumor-infiltrating immune cells from esophageal squamous cell carcinoma (ESCC) TME and analyzed IL-32 expression in different immune cell types. We found CD4(+) regulatory T cells (Treg cells) express the highest level of IL-32, while proliferating T and natural killer cells expressed relatively lower levels. Knocking down of IL-32 reduced Foxp3 and interferon gamma (IFNγ) expressions in CD4(+) and CD8(+) T cells, respectively. IL-32 was positively correlated with Foxp3, IFNG, and GZMB expression but was negatively correlated with proliferation score. IL-32 may have a contradictory role in the TME such as it promotes IFNγ expression in CD8(+) T cells, which enhances the antitumor activity, but at the same time induces Foxp3 expression in CD4(+) T cells, which suppresses the tumor immune response. Our results demonstrate different roles of IL-32 in Treg cells and CD8(+) T cells and suggest that it can potentially be a target for ESCC cancer immunosuppressive therapy.