| Title: | Tumor-derived interleukin-34 creates an immunosuppressive and chemoresistant tumor microenvironment by modulating myeloid-derived suppressor cells in triple-negative breast cancer |
| Authors: | Kajihara, Nabeel Browse this author |
| Kobayashi, Takuto Browse this author |
| Otsuka, Ryo Browse this author |
| Nio-Kobayashi, Junko Browse this author |
| Oshino, Tomohiro Browse this author |
| Takahashi, Masato Browse this author |
| Imanishi, Seiichi Browse this author |
| Hashimoto, Ari Browse this author →KAKEN DB |
| Wada, Haruka Browse this author →KAKEN DB |
| Seino, Ken-ichiro Browse this author →KAKEN DB |
| Keywords: | Interleukin-34 |
| Triple-negative breast cancer |
| Myeloid-derived suppressor cells |
| 4T1 |
| Tumor microenvironment |
| Chemotherapy |
| Issue Date: | 1-Apr-2023 |
| Publisher: | Springer |
| Journal Title: | Cancer immunology immunotherapy |
| Volume: | 72 |
| Issue: | 4 |
| Start Page: | 851 |
| End Page: | 864 |
| Publisher DOI: | 10.1007/s00262-022-03293-3 |
| Abstract: | 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. |
| Rights: | 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 |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/92062 |
| Appears in Collections: | 遺伝子病制御研究所 (Institute for Genetic Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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