On November 25, a research group led by Professor Norimitsu Inoue and Lecturer Takashi Baba of the Department of Molecular Genetics and Professor Isao Hara and Assistant Professor Satoshi Muraoka of the Department of Urology at Wakayama Medical University School of Medicine announced their research results showing that a high lactic acid environment within tumors suppresses intratumoral immune response to bladder cancer through histone acetylation. They confirmed that lactic acid stimulation enhanced acetylation at lysine 27 of histone H3 in B cells, and inhibition of this pathway resulted in suppression of tumor growth in mouse bladder cancer. They also showed that the aforementioned acetylation was also promoted by indirect non-B cell effects. These findings are expected to contribute to developing a new therapeutic strategy for urological tumors. The results were published in the October 31 issue of the International Journal of Cancer.
Provided by Wakayama Medical University
A high lactic acid environment is established in tumors due to a specific enhancement of glycolysis (the Warburg effect). Recently, high-level lactic acid in tumors (tumor microenvironment) has been reported to affect immune cells, possibly suppressing anti-tumor immunity and causing tumor growth. Meanwhile, numerous types of immune cells are affected by lactic acid, and the effects are not understood in detail.
In this study, in order to investigate the effects of lactic acid stimulation on a wide range of immune cells, the research group first analyzed the effects of lactic acid stimulation on splenocytes, which comprise various immune cells, with a focus on histones.
Acetylation at lysine 27 of histone H3 (H3K27ac) was specifically enhanced when mouse splenocytes were cultured under high lactic acid conditions. In particular, H3K27ac was markedly enhanced nearly two-fold in B cells. Since H3K27ac is a marker of enhanced gene expression, transcription was considered to be enhanced. Therefore, they examined whether the interaction with CD40, which is expressed on the surface of B cells and is involved in the activation of these cells, was involved in H3K27ac.
The results showed that acetylation was increased by lactic acid stimulation but decreased by inhibitory antibodies. Activation of CD40 was found to be important for the increase in acetylation. Then, the research team focused on G protein-coupled receptors on the plasma membrane as signaling pathways that may promote the aforementioned acetylation. They explored these downstream signaling pathways and found the involvement of EPAC1/2 (guanine nucleotide exchange factors) activation. In addition, the aforementioned acetylation was shown to be promoted through the activation of EPAC1/2 signaling mediated by immune cells other than B cells.
The effects of an EPAC1/2 inhibitor on the bladder and renal cancers transplanted into mice were examined in terms of acetylation in tumor-infiltrating B cells and its effects on tumor cells, and significant decreases in acetylation and tumor growth suppression were observed only in bladder cancer-bearing mice. Furthermore, changes in gene expression upon lactic acid stimulation were examined with a focus on chemokines and cytokines. Only B cells were purified from mouse spleens, and the changes induced by lactic acid stimulation were analyzed by RNA-seq.
The results confirmed a significant increase in IL10, suppressing the intratumoral immune response. They also confirmed that the lactic acid-dependent increase in IL10 was suppressed by an EPAC1/2 inhibitor. Moving forward, they will search for factors downstream of EPAC1/2 and conduct inhibition experiments to bring this therapeutic strategy closer to actual clinical practice.
Journal Information
Publication: International Journal of Cancer
Title: Tumor-derived lactic acid promotes acetylation of histone H3K27 and differentiation of IL-10-producing regulatory B cells through direct and indirect signaling pathways
DOI: 10.1002/ijc.35229
This article has been translated by JST with permission from The Science News Ltd. (https://sci-news.co.jp/). Unauthorized reproduction of the article and photographs is prohibited.