A mechanism of cooling hot tumors: Lactate attenuates inflammation in dendritic cells

Hisashi Kanemaru; Yukari Mizukami; Akira Kaneko; Hidemi Tagawa; Toshihiro Kimura; Haruka Kuriyama; Soichiro Sawamura; Ikko Kajihara; Katsunari Makino; Azusa Miyashita; Jun Aoi; Takamitsu Makino; Shinichi Masuguchi; Satoshi Fukushima; Hironobu Ihn

iScience (Sep 2021)

A mechanism of cooling hot tumors: Lactate attenuates inflammation in dendritic cells

Hisashi Kanemaru,
Yukari Mizukami,
Akira Kaneko,
Hidemi Tagawa,
Toshihiro Kimura,
Haruka Kuriyama,
Soichiro Sawamura,
Ikko Kajihara,
Katsunari Makino,
Azusa Miyashita,
Jun Aoi,
Takamitsu Makino,
Shinichi Masuguchi,
Satoshi Fukushima,
Hironobu Ihn

Affiliations

Hisashi Kanemaru: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan; Corresponding author
Yukari Mizukami: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan
Akira Kaneko: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan
Hidemi Tagawa: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan
Toshihiro Kimura: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan
Haruka Kuriyama: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan
Soichiro Sawamura: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan
Ikko Kajihara: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan
Katsunari Makino: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan
Azusa Miyashita: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan
Jun Aoi: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan
Takamitsu Makino: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan
Shinichi Masuguchi: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan
Satoshi Fukushima: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan
Hironobu Ihn: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Japan

Journal volume & issue: Vol. 24, no. 9
p. 103067

Abstract

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Summary: Turning non-inflamed (cold) tumors into inflamed (hot) tumors is important for maximizing the effect of immune checkpoint inhibitors (ICIs) against malignancies. 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, lactate promoted the expression of early growth response protein 1 (EGR1), whose expression was increased in human invasive melanoma compared with non-invasive melanoma. We also found that EGR1 interacts with serum response factor (SRF) and represses the expression of CD80 in DCs. These findings suggest that lactate and its induced EGR1 are key factors that turn hot tumors into cold tumors and may represent targets in cancer treatment with ICIs.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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