Tumor-derived interleukin-34 creates an immunosuppressive and chemoresistant tumor microenvironment by modulating myeloid-derived suppressor cells in triple-negative breast cancer
Tumor-derived interleukin-34 creates an immunosuppressive and chemoresistant tumor microenvironment by modulating myeloid-derived suppressor cells in triple-negative breast cancer
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DOI：
10.1007/s00262-022-03293-3
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发表时间：
2022-09-14
影响因子：
5.8
通讯作者：
Seino, Ken-ichiro
中科院分区：
文献类型：
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作者：
Kajihara, Nabeel;Kobayashi, Takuto;Seino, Ken-ichiro
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，其特征是缺乏治疗靶点。由于缺乏有效的治疗方案，许多研究都致力于解决这一问题。免疫抑制细胞浸润到TNBC的肿瘤微环境（TME）目前被认为是新的治疗靶点的候选者。据报道，髓源性抑制细胞（MDSCs）在TNBC的TME中填充，但它们在TNBC的临床和生物学特征中的作用尚未明确。本研究发现TNBC细胞释放的白细胞介素-34 （IL-34）是调节TME中MDSCs积累的重要免疫调节剂。我们提供的证据表明，IL-34诱导髓系干细胞分化为单核细胞MDSCs (M-MDSCs)，募集调节性T细胞（Treg），同时抑制分化为多形核MDSCs （PMN-MDSCs）。因此，M-MDSCs的增加有助于免疫抑制性TME的产生，PMN-MDSCs的减少抑制血管生成，导致获得对化疗的耐药性。因此，用雌激素受体抑制剂或抗il -34单克隆抗体阻断M-MDSC分化可抑制M-MDSCs的积累，从而延缓肿瘤生长，并通过促进PMN-MDSCs的积累来恢复肿瘤的化学敏感性。本研究揭示了mdscs介导的TNBC TME耐药机制，该机制源于IL-34的存在，为TNBC治疗提供了新的理论依据。
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.