Tumor-Derived Lactic Acid Contributes to the Paucity of Intratumoral ILC2s

Marek Wagner; Kafi N Ealey; Hiroe Tetsu; Tsuyoshi Kiniwa; Yasutaka Motomura; Kazuyo Moro; Shigeo Koyasu

doi:10.1016/j.celrep.2020.01.103

Tumor-Derived Lactic Acid Contributes to the Paucity of Intratumoral ILC2s

Cell Rep. 2020 Feb 25;30(8):2743-2757.e5. doi: 10.1016/j.celrep.2020.01.103.

Authors

Marek Wagner¹, Kafi N Ealey², Hiroe Tetsu³, Tsuyoshi Kiniwa², Yasutaka Motomura⁴, Kazuyo Moro⁵, Shigeo Koyasu⁶

Affiliations

¹ Laboratory for Immune Cell Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Laboratory for Innate Immune Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Biomedicine, University of Bergen, Bergen, Norway. Electronic address: marek.wagner@uib.no.
² Laboratory for Innate Immune Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
³ Laboratory for Innate Immune Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Medical Life Science, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan.
⁴ Laboratory for Innate Immune Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Laboratory for Innate Immune Systems, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.
⁵ Laboratory for Innate Immune Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Medical Life Science, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan; Laboratory for Innate Immune Systems, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan; Laboratory for Innate Immune Systems, Immunology Frontier Research Center (IFReC), Osaka University Graduate School of Medicine, Osaka, Japan.
⁶ Laboratory for Immune Cell Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan. Electronic address: shigeo.koyasu@riken.jp.

PMID: 32101749
DOI: 10.1016/j.celrep.2020.01.103

Abstract

Group 2 innate lymphoid cells (ILC2s) are abundant in non-lymphoid tissues and increase following infectious and inflammatory insults. In solid tumors, however, ILC2s constitute a relatively small proportion of immune cells. Here, we show, using melanoma as a model, that while the IL-33/IL C2/eosinophil axis suppresses tumor growth, tumor-derived lactate attenuates the function and survival of ILC2s. Melanomas with reduced lactate production (LDHA^low) are growth delayed and typified by an increased number of ILC2s compared with control tumors. Upon IL-33 stimulation, ILC2s accompanied by eosinophils more effectively restrain the growth of LDHA^low tumors than control melanomas. Furthermore, database analysis reveals a negative correlation between the expression of LDHA and markers associated with ILC2s and the association of high expression of IL33 and an eosinophil marker SIGLEC8 with better overall survival in human cutaneous melanoma patients. This work demonstrates that the balance between the IL-33/ILC2/eosinophil axis and lactate production by tumor cells regulates melanoma growth.

Keywords: IL-33; ILC2; Warburg effect; antitumor immunity; eosinophil; lactic acid; melanoma; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Proliferation
Cell Survival
Eosinophils / immunology
Female
Humans
Immunity, Innate*
Interleukin-33 / metabolism
Interleukin-5 / biosynthesis
L-Lactate Dehydrogenase / metabolism
Lactic Acid / metabolism*
Lymphocytes / immunology*
Male
Melanoma, Experimental / immunology*
Melanoma, Experimental / pathology
Mice, Inbred C57BL
Skin Neoplasms / immunology*

Substances

Interleukin-33
Interleukin-5
Lactic Acid
L-Lactate Dehydrogenase