Tumors with an inflamed tumor microenvironment are considered “hot tumors” and show good responses to immune checkpoint inhibitors (ICIs). Conversely, non-inflamed tumors, so-called “cold tumors,” have no tumor-suppressive cytokines and rarely respond to ICIs. Therefore, turning non-inflamed (cold) tumors into inflamed (hot) tumors is important for maximizing the effect of ICIs. We showed that lactate, a product of the Warburg effect, inhibited the efficacy of ICIs and suppressed IL-12 p40 expression in dendritic cells (DCs) through reducing NF-κB p65, p50 and c-Rel DNA-binding activity to the IL-12 p40 promoter. Additionally, microarray analyses showed that lactate promoted the expression of early growth response protein 1 (EGR1). Using a mouse tumor model, we found the expression of EGR1 was higher in DCs in B16-F1 cell-derived tumors compared with other immune cells or tumor cells. We also found that the expression of EGR1 was significantly increased in human invasive melanoma compared with non-invasive melanoma. Additionally, the expression levels of EGR1 were correlated with tumor thickness and 5-S-CD, which is a common tumor marker for melanoma. Although there were no significant differences in the expression levels of IL-12 p40 between Egr1−/− and WT DCs, ChIP-Seq analysis showed a region that suggested the interaction of EGR1 in the CD80 promoter. We also found that EGR1 interacts with serum response factor (SRF) and represses the expression of CD80 in DCs. Taken together, these results suggested that the expression of IL-12 p40 can be suppressed by lactate but this is independent of EGR1, while the expression of CD80 may be dependent on both lactate and EGR1, which is induced by lactate. In conclusion, our results suggest that lactate and its induced EGR1 may be novel key factors that determine the inflamed or non-inflamed tumor status and may be new targets for stimulating antitumor immunity in treatment with ICIs.

ESDR444 - Lactate and its induced EGR1 are novel key factors that turn hot tumors into cold tumors

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.