Tumor-derived interleukin-34 creates an immunosuppressive and chemoresistant tumor microenvironment by modulating myeloid-derived suppressor cells in triple-negative breast cancer

Kajihara, Nabeel; Kobayashi, Takuto; Otsuka, Ryo; Nio-Kobayashi, Junko; Oshino, Tomohiro; Takahashi, Masato; Imanishi, Seiichi; Hashimoto, Ari; Wada, Haruka; Seino, Ken-ichiro

Tumor-derived interleukin-34 creates an immunosuppressive and chemoresistant tumor microenvironment by modulating myeloid-derived suppressor cells in triple-negative breast cancer

Kajihara, Nabeel; Kobayashi, Takuto; Otsuka, Ryo et al.

Cancer immunology immunotherapy, 2023, 72(4), 851-864

Permalink : https://hdl.handle.net/2115/92062

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アクセス権	open access
URI	https://hdl.handle.net/2115/92062
タイトル	Tumor-derived interleukin-34 creates an immunosuppressive and chemoresistant tumor microenvironment by modulating myeloid-derived suppressor cells in triple-negative breast cancer
著者	Kajihara, Nabeel ; Kobayashi, Takuto ; Otsuka, Ryo ; Nio-Kobayashi, Junko ; Oshino, Tomohiro ; Takahashi, Masato ; Imanishi, Seiichi ; Hashimoto, Ari ; Wada, Haruka ; Seino, Ken-ichiro
著者名 Kajihara, Nabeel
著者名 Kobayashi, Takuto
著者名 Otsuka, Ryo
著者名 Nio-Kobayashi, Junko
著者名 Oshino, Tomohiro
著者名 Takahashi, Masato
著者名 Imanishi, Seiichi
e-Rad_Researcher 60390803 著者名 Hashimoto, Ari
e-Rad_Researcher 70392181 著者名 Wada, Haruka
e-Rad_Researcher 20312845 著者名 Seino, Ken-ichiro
言語	英語
キーワード	Interleukin-34
	Triple-negative breast cancer
	Myeloid-derived suppressor cells
	4T1
	Tumor microenvironment
	Chemotherapy
発行日	2023-04-01
出版者	Springer
収録物名	Cancer immunology immunotherapy
巻(号)	72(4)
ページ	851-864
抄録	Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by a lack of therapeutic targets. The paucity of effective treatment options motivated a number of studies to tackle this problem. Immunosuppressive cells infiltrated into the tumor microenvironment (TME) of TNBC are currently considered as candidates for new therapeutic targets. Myeloid-derived suppressor cells (MDSCs) have been reported to populate in the TME of TNBC, but their roles in the clinical and biological features of TNBC have not been clarified. This study identified that interleukin-34 (IL-34) released by TNBC cells is a crucial immunomodulator to regulate MDSCs accumulation in the TME. We provide evidence that IL-34 induces a differentiation of myeloid stem cells into monocytic MDSCs (M-MDSCs) that recruits regulatory T (Treg) cells, while suppressing a differentiation into polymorphonuclear MDSCs (PMN-MDSCs). As a result, the increase in M-MDSCs contributes to the creation of an immunosuppressive TME, and the decrease in PMN-MDSCs suppresses angiogenesis, leading to an acquisition of resistance to chemotherapy. Accordingly, blockade of M-MDSC differentiation with an estrogen receptor inhibitor or anti-IL-34 monoclonal antibody suppressed M-MDSCs accumulation causing retardation of tumor growth and restores chemosensitivity of the tumor by promoting PMN-MDSCs accumulation. This study demonstrates previously poorly understood mechanisms of MDSCs-mediated chemoresistance in the TME of TNBC, which is originated from the existence of IL-34, suggesting a new rationale for TNBC treatment.
資源タイプ	学術雑誌論文
出版タイプ	Accepted Manuscript
権利情報	This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: http://dx.doi.org/10.1007/s00262-022-03293-3
PISSN	0340-7004
関連情報 (isVersionOf)	出版社版DOI https://doi.org/10.1007/s00262-022-03293-3