Department of Microbiology and Immunology, Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran.
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Front Immunol. 2021 Feb 19;11:613215. doi: 10.3389/fimmu.2020.613215. eCollection 2020.
Cancer cells escape immune destruction. From this perspective, myeloid-derived suppressor cells (MDSCs), which are immunosuppressive in various cancers including breast cancer (BC), are significant. However, the precise mechanisms are unknown. We isolated HLA-DRCD33 MDSCs and CD3 T cells from BC patients' peripheral blood and healthy donors through MACS and immunophenotyped by flow cytometry. Transfection of short-interfering RNAs and treatment with a TLR7/8 agonist altered pathway activities . Gene expression was analyzed using qRT-PCR, western blotting, and immunohistochemistry. Our findings showed an association between the progression of BC and increased levels of circulating HLA-DRCD33 MDSCs. These cells strongly suppress both autologous and analogous CD3 T cell proliferation and enter the tumor microenvironment. We also identified increased STAT3 signaling and increased IDO and IL-10 expression in BC-derived MDSCs as immunosuppression mechanisms. Further, STAT3 inhibition and TLR7/8 pathway stimulation reduce the immunosuppressive activity of patient-derived MDSCs on T cells by inducing MDSC repolarization and differentiation into mature myeloid cells. This also alters the expression of critical cytokines and transcription factors in CD3 T cells and, importantly, reduces breast cancer cells' proliferation. Finally, while chemotherapy is able to significantly reduce circulating MDSCs' level in patients with breast cancer, these MDSCs remained highly T cell-suppressive. We identified a novel molecular mechanism of MDSC-mediated immunosuppression. STAT3 inhibition and TLR7/8 pathway stimulation in MDSCs repolarize and suppress MDSCs from breast cancer patients. This offers new opportunities for BC immunotherapy.
癌细胞逃避免疫破坏。从这个角度来看，髓系来源的抑制性细胞（MDSCs）在包括乳腺癌（BC）在内的各种癌症中具有免疫抑制作用，因此具有重要意义。然而，确切的机制尚不清楚。我们通过 MACS 从 BC 患者和健康供体的外周血中分离出 HLA-DRCD33 MDSCs 和 CD3 T 细胞，并通过流式细胞术进行免疫表型分析。转染小干扰 RNA 和 TLR7/8 激动剂处理改变了通路活性。使用 qRT-PCR、western blot 和免疫组织化学分析基因表达。我们的研究结果表明，BC 的进展与循环 HLA-DRCD33 MDSCs 水平的升高有关。这些细胞强烈抑制自体和类似 CD3 T 细胞的增殖，并进入肿瘤微环境。我们还发现，BC 衍生的 MDSCs 中 STAT3 信号的增加以及 IDO 和 IL-10 的表达增加是其免疫抑制机制。此外，STAT3 抑制和 TLR7/8 通路的刺激通过诱导 MDSC 重极化和分化为成熟的髓系细胞来减少患者来源的 MDSC 对 T 细胞的抑制活性。这也改变了 CD3 T 细胞中关键细胞因子和转录因子的表达，并重要的是，减少了乳腺癌细胞的增殖。最后，虽然化疗能够显著降低乳腺癌患者循环 MDSCs 的水平，但这些 MDSCs仍然具有很强的 T 细胞抑制作用。我们确定了 MDSC 介导的免疫抑制的新分子机制。STAT3 抑制和 TLR7/8 通路刺激 MDSC 重极化并抑制来自乳腺癌患者的 MDSC。这为乳腺癌的免疫治疗提供了新的机会。
