IL36G-producing neutrophil-like monocytes promote cachexia in cancer

Yoshihiro Hayashi (), Yasushige Kamimura-Aoyagi, Sayuri Nishikawa, Rena Noka, Rika Iwata, Asami Iwabuchi, Yushin Watanabe, Natsumi Matsunuma, Kanako Yuki, Hiroki Kobayashi, Yuka Harada and Hironori Harada ()
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Yoshihiro Hayashi: Tokyo University of Pharmacy and Life Sciences
Yasushige Kamimura-Aoyagi: Tokyo University of Pharmacy and Life Sciences
Sayuri Nishikawa: Tokyo University of Pharmacy and Life Sciences
Rena Noka: Tokyo University of Pharmacy and Life Sciences
Rika Iwata: Tokyo University of Pharmacy and Life Sciences
Asami Iwabuchi: Tokyo University of Pharmacy and Life Sciences
Yushin Watanabe: Tokyo University of Pharmacy and Life Sciences
Natsumi Matsunuma: Tokyo University of Pharmacy and Life Sciences
Kanako Yuki: Tokyo University of Pharmacy and Life Sciences
Hiroki Kobayashi: Tokyo University of Pharmacy and Life Sciences
Yuka Harada: Komagome Hospital
Hironori Harada: Tokyo University of Pharmacy and Life Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Most patients with advanced cancer develop cachexia, a multifactorial syndrome characterized by progressive skeletal muscle wasting. Despite its catastrophic impact on survival, the critical mediators responsible for cancer cachexia development remain poorly defined. Here, we show that a distinct subset of neutrophil-like monocytes, which we term cachexia-inducible monocytes (CiMs), emerges in the advanced cancer milieu and promotes skeletal muscle loss. Unbiased transcriptome analysis reveals that interleukin 36 gamma (IL36G)-producing CD38+ CiMs are induced in chronic monocytic blood cancer characterized by prominent cachexia. Notably, the emergence of CiMs and the activation of CiM-related gene signatures in monocytes are confirmed in various advanced solid cancers. Stimuli of toll-like receptor 4 signaling are responsible for the induction of CiMs. Genetic inhibition of IL36G-mediated signaling attenuates skeletal muscle loss and rescues cachexia phenotypes in advanced cancer models. These findings indicate that the IL36G-producing subset of neutrophil-like monocytes could be a potential therapeutic target in cancer cachexia.

Date: 2024
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DOI: 10.1038/s41467-024-51873-x

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