Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth.

Glucocorticoids are steroid hormones with potent immunosuppressive properties. Their primary source is the adrenals, where they are generated via de novo synthesis from cholesterol. In addition, many tissues have a recycling pathway in which glucocorticoids are regenerated from inactive metabolites by the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1, encoded by Hsd11b1). Here, we find that multiple tumor types express Hsd11b1 and produce active glucocorticoids. Genetic ablation of Hsd11b1 in such cells had no effect on in vitro growth, but reduced in vivo tumor progression, which corresponded with increased frequencies of CD8+ tumor-infiltrating lymphocytes (TILs) expressing activation markers and producing effector cytokines. Tumor-derived glucocorticoids were found to promote signatures of Treg activation and suppress signatures of conventional T cell activation in tumor-infiltrating Tregs. Indeed, CD8+ T cell activation was restored and tumor growth reduced in mice with Treg-specific glucocorticoid receptor deficiency. Importantly, pharmacologic inhibition of 11ß-HSD1 reduced tumor growth to the same degree as gene knockout and rendered immunotherapy-resistant tumors susceptible to PD-1 blockade. Given that HSD11B1 expression is upregulated in many human tumors and that inhibition of 11ß-HSD1 is well tolerated in clinical studies, these data suggest that targeting 11ß-HSD1 may be a beneficial adjunct in cancer therapy.

Color discrimination thresholds in a cichlid fish: Metriaclima benetos.

Color vision is essential for animals as it allows them to detect, recognize and discriminate between colored objects. Studies analyzing color vision require an integrative approach, combining behavioral experiments, physiological models and quantitative analyses of photoreceptor stimulation. Here, we demonstrate, for the first time, the limits of chromatic discrimination in Metriaclima benetos, a rock-dwelling cichlid from Lake Malawi, using behavioral experiments and visual modeling. Fish were trained to discriminate between colored stimuli. Color discrimination thresholds were quantified by testing fish chromatic discrimination between the rewarded stimulus and distracter stimuli that varied in chromatic distance (ΔS). This was done under fluorescent lights alone and with additional violet lights. Our results provide two main outcomes. First, cichlid color discrimination thresholds correspond with predictions from the receptor noise limited (RNL) model but only if we assume a Weber fraction higher than the typical value of 5%. Second, cichlids may exhibit limited color constancy under certain lighting conditions as most individuals failed to discriminate colors when violet light was added. We further used the color discrimination thresholds obtained from these experiments to model color discrimination of actual fish colors and backgrounds under natural lighting for Lake Malawi. We found that, for M. benetos, blue is most chromatically contrasting against yellows and space-light, which might be important for discriminating male nuptial colorations and detecting males against the background. This study highlights the importance of lab-based behavioral experiments in understanding color vision and in parameterizing the assumptions of the RNL vision model for different species.