TLR9-Targeted STAT3 Silencing Abrogates Immunosuppressive Activity of Myeloid-Derived Suppressor Cells from Prostate Cancer Patients.
TLR9-Targeted STAT3 Silencing Abrogates Immunosuppressive Activity of Myeloid-Derived Suppressor Cells from Prostate Cancer Patients.
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DOI：
10.1158/1078-0432.ccr-14-3145
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发表时间：
2015-08-15
期刊：
影响因子：
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通讯作者：
Kortylewski M
中科院分区：
文献类型：
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作者：
Hossain DM;Pal SK;Moreira D;Duttagupta P;Zhang Q;Won H;Jones J;D'Apuzzo M;Forman S;Kortylewski M
晚期人类癌症免疫治疗的最新进展强调了解决和消除肿瘤免疫逃避的必要性。骨髓源性抑制细胞（MDSC）是实体瘤（如前列腺癌）中T细胞应答的重要抑制剂。然而，由于MDSC的表型异质性，靶向MDSC被证明具有挑战性。对健康受试者、局部和转移性去势抵抗性前列腺癌患者的血液样本采用流式细胞术、功能测定和肿瘤/肿瘤引流淋巴结标本的免疫组织化学/免疫荧光染色评价骨髓细胞群。在这里，我们确定了一个群体的Lin-CD 15 β D33 LO粒细胞MDSC，积累在患者的循环过程中，前列腺癌从局部到转移性疾病的进展。前列腺癌相关MDSC有效抑制自体CD 8 + T细胞增殖和IFNγ和颗粒酶-B的产生。循环MDSC具有高水平的活化的STAT 3，其是中枢免疫检查点调节剂。在患者的前列腺组织中也可检测到粒细胞pSTAT 3+细胞。我们以前产生了一个原始的策略沉默基因特异性Toll样受体-9（TLR 9）阳性骨髓细胞使用CpG-siRNA共轭。我们证明，人粒细胞MDSC表达TLR 9，并迅速内化裸CpG-STAT 3siRNA，从而沉默STAT 3表达。STAT 3阻断消除了患者来源的MDSC对效应CD 8 + T细胞的免疫抑制作用。这些作用依赖于精氨酸酶-1的表达和酶活性降低，精氨酸酶-1是下游STAT 3靶基因和有效的T细胞抑制剂。总之，我们证明了粒细胞MDSC的积累与前列腺癌的进展和使用TLR 9靶向STAT 3siRNA递送策略来减轻MDSC介导的免疫抑制的可行性。
Recent advances in immunotherapy of advanced human cancers underscored the need to address and eliminate tumor immune evasion. The myeloid-derived suppressor cells (MDSCs) are important inhibitors of T cell responses in solid tumors, such as prostate cancers. However, targeting MDSCs proved challenging due to their phenotypic heterogeneity. Myeloid cell populations were evaluated using flow cytometry on blood samples, functional assays and immunohistochemical/immunofluorescent stainings on tumor/tumor-draining lymph node specimens from healthy subjects, localized and metastatic castration-resistant prostate cancer patients. Here, we identify a population of Lin−CD15HICD33LO granulocytic MDSCs that accumulate in patients’ circulation during prostate cancer progression from localized to metastatic disease. The prostate cancer-associated MDSCs potently inhibit autologous CD8+ T cells proliferation and production of IFNγ and Granzyme-B. The circulating MDSCs have high levels of activated STAT3, which is a central immune checkpoint regulator. The granulocytic pSTAT3+ cells are also detectable in patients’ prostate tissues. We previously generated an original strategy to silence genes specifically in Toll-like Receptor-9 (TLR9) positive myeloid cells using CpG-siRNA conjugates. We demonstrate that human granulocytic MDSCs express TLR9 and rapidly internalize naked CpG-STAT3siRNA thereby silencing STAT3 expression. STAT3 blocking abrogates immunosuppressive effects of patients-derived MDSCs on effector CD8+ T cells. These effects depended on reduced expression and enzymatic activity of Arginase-1, a downstream STAT3 target gene and a potent T cell inhibitor. Overall, we demonstrate the accumulation of granulocytic MDSCs with prostate cancer progression and the feasibility of using TLR9-targeted STAT3siRNA delivery strategy to alleviate MDSC-mediated immunosuppression.