Tumors recycle glucocorticoids to drive Treg-mediated immunosuppression

Abstract

Suppression of antitumor immunity is a prominent feature of the tumor microenvironment. In this issue of the JCI, Taves, Otsuka, and authors show that glucocorticoids (GCs), which are potent immunosuppressive hormones mainly produced by the adrenals, can be reconverted from their inactive form to active metabolites via the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme expressed by murine tumor cell lines. In the tumor microenvironment, GCs acted on CD4+ regulatory T cells to enhance their immunosuppressive function and promote tumor growth. The findings suggest that targeting GC recycling as a strategy for modulating tumor immunosuppression has the potential to improve therapeutic efficacy of immune checkpoint blockade.

Figure 1. Tumors recycle GCs to drive Treg-mediated immunosuppression.

The murine B16 tumor cell lines express 11β-HSD1 to convert inactive GCs to their active metabolites (6). Within the tumor microenvironment of immunocompetent mice, GCs act on CD4⁺ Tregs to enhance their immunosuppressive function (6) and on CD8⁺ T cells to impede function (2), thereby promoting tumor growth. 11β-HSD1–producing B16 tumor cells in Rag2-deficient mice, which lack T and B cells, cease to expand, suggesting that GCs act locally on adaptive immune cells to promote tumor growth.