Academic Thesis

Basic information

Name Katayama Keiichi
Belonging department
Occupation name
researchmap researcher code B000305947
researchmap agency Okayama University of Science

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

Bibliography Type

 

Author

Satoshi Muraoka
Takashi Baba
Takashi Akazawa
Kei‐ichi Katayama
Hiroki Kusumoto
Shimpei Yamashita
Yasuo Kohjimoto
Sadahiro Iwabuchi
Shinichi Hashimoto
Isao Hara
Norimitsu Inoue

Summary

Abstract

Tumor cells are known to enhance glycolysis, even under normoxic conditions, via the Warburg effect, producing excess lactic acid in the tumor microenvironment. Lactic acid enhances the IL‐23/IL‐17 pathway and induces chronic inflammation. The acidic microenvironment formed by lactic acid suppresses immune cell proliferation and activation. In the present study, we clarified that lactic acid had two novel activities for immune cells. First, lactic acid specifically enhanced acetylation at lysine 27 of histone H3 (H3K27ac) in splenic B cells and monocytes/macrophages, and this epigenetically up‐regulates the expression of genes. Acetylation and methylation of other residues of histone H3 were rarely induced. Second, lactic acid induced a particularly‐marked enhancement of Il10 gene expression in B cells, leading to an increase in IL‐10‐producing regulatory B (Breg) cells. Furthermore, two pathways should be involved in both the enhancement of H3K27ac and the induction of Breg cells by lactic acid: a direct pathway that enhances the CD40 signal in B cells, and an indirect pathway that affects B cells by activating the exchange protein directly activated by cAMP (EPAC) 1/2 in non‐B cells. In tumor‐bearing mice, the levels of H3K27ac of tumor‐infiltrating B cells were significantly higher than splenic B cells and were suppressed by intraperitoneal injection of the EPAC1/2 inhibitor. In conclusion, tumor‐derived lactic acid increases H3K27ac and IL‐10‐producing Breg cells, causing the suppression of anti‐tumor immunity.

Magazine(name)

International Journal of Cancer

Publisher

Wiley

Volume

156

Number Of Pages

4

StartingPage

840

EndingPage

852

Date of Issue

2024-10-31

Referee

Exist

Invited

 

Language

 

Thesis Type

Research papers (academic journals)

ISSN

 

DOI

10.1002/ijc.35229

NAID

 

PMID

 

J-GLOBAL ID

 

arXiv ID

 

ORCID Put Code

 

DBLP ID