Immunostimulatory RNA leads to functional reprogramming of myeloid-derived suppressor cells in pancreatic cancer
Immunostimulatory RNA leads to functional reprogramming of myeloid-derived suppressor cells in pancreatic cancer
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DOI：
10.1186/s40425-019-0778-7
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发表时间：
2019-11-06
影响因子：
10.9
通讯作者：
Duewell, Peter
中科院分区：
文献类型：
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作者：
Metzger, Philipp;Kirchleitner, Sabrina, V;Duewell, Peter
背景肿瘤微环境(TME)结合了调节性细胞因子和免疫细胞群的特征，以逃避免疫系统的识别。髓系细胞来源的抑制细胞(MDSC)包括肿瘤宿主中具有高度免疫抑制能力的未成熟髓系细胞群。RIG-I样解旋酶(RIH)是诱导免疫原性肿瘤细胞死亡的胰腺癌免疫治疗的靶点，I型干扰素(IFN)是连接天然免疫和获得性免疫的关键介质。方法采用Kras(G12D)P53(F1/R172H)Ptf1a-Cre(KPC)原位移植瘤小鼠，静脉注射RLH型多肌胞苷多胞苷(Poly(I：C))，观察肿瘤和脾的免疫细胞环境。对分离的MDSC亚群的抑制能力以及整个转录图谱进行了全面的分析。在T细胞增殖实验中检测卵蛋白(OVA)表达肿瘤小鼠骨髓间充质干细胞的抗原提呈能力。用Ifnar1(-/-)小鼠观察干扰素对MDSC功能的影响。结果KPC来源的原位胰腺癌可强烈诱导MDSC，且MDSC亚群频率与肿瘤重量和血清G-CSF水平相关，而其他免疫细胞亚群减少。给予rlh配体诱导了干扰素驱动的免疫反应，T细胞和树突状细胞(DC)的激活增加，而多形核(PMN)-MDSC和单核(M)-MDSC组分的抑制能力降低。完整的转录分析证实了MDSC由干扰素驱动的基因特征，从M2/G2-到M1/G1-极化的表型转换，以及参与抗原呈递机制的基因的诱导。然而，MDSC不能将肿瘤抗原呈递给T细胞。有趣的是，我们发现在Ifnar1缺陷的宿主中，MDSC的抑制功能降低；然而，在免疫细胞激活方面存在一个共同的缺陷，这反映在免疫细胞激活和肿瘤控制方面的缺陷。结论免疫刺激RNA治疗可降低MDSC的抑制活性，使髓系细胞极化为类M1状态，并募集DC，从而重塑胰腺癌的TME。我们推测，肿瘤细胞靶向组合策略可能受益于基于RLH的TME重塑。此外，我们对干扰素信号在MDSC抑制功能中的双重作用提供了新的见解，并为宿主内源性干扰素信号可能是MDSC在肿瘤发展过程中获得抑制功能的关键提供了证据。
Background The tumor microenvironment (TME) combines features of regulatory cytokines and immune cell populations to evade the recognition by the immune system. Myeloid-derived suppressor cells (MDSC) comprise populations of immature myeloid cells in tumor-bearing hosts with a highly immunosuppressive capacity. We could previously identify RIG-I-like helicases (RLH) as targets for the immunotherapy of pancreatic cancer inducing immunogenic tumor cell death and type I interferons (IFN) as key mediators linking innate with adaptive immunity. Methods Mice with orthotopically implanted Kras(G12D) p53(fl/R172H) Ptf1a-Cre (KPC) pancreatic tumors were treated intravenously with the RLH ligand polyinosinic-polycytidylic acid (poly(I:C)), and the immune cell environment in tumor and spleen was characterized. A comprehensive analysis of the suppressive capacity as well as the whole transcriptomic profile of isolated MDSC subsets was performed. Antigen presentation capability of MDSC from mice with ovalbumin (OVA)-expressing tumors was investigated in T cell proliferation assays. The role of IFN in MDSC function was investigated in Ifnar1(-/-) mice. Results MDSC were strongly induced in orthotopic KPC-derived pancreatic cancer, and frequencies of MDSC subsets correlated with tumor weight and G-CSF serum levels, whereas other immune cell populations decreased. Administration of the RLH-ligand induced a IFN-driven immune response, with increased activation of T cells and dendritic cells (DC), and a reduced suppressive capacity of both polymorphonuclear (PMN)-MDSC and monocytic (M)-MDSC fractions. Whole transcriptomic analysis confirmed an IFN-driven gene signature of MDSC, a switch from a M2/G2- towards a M1/G1-polarized phenotype, and the induction of genes involved in the antigen presentation machinery. Nevertheless, MDSC failed to present tumor antigen to T cells. Interestingly, we found MDSC with reduced suppressive function in Ifnar1-deficient hosts; however, there was a common flaw in immune cell activation, which was reflected by defective immune cell activation and tumor control. Conclusions We provide evidence that the treatment with immunostimulatory RNA reprograms the TME of pancreatic cancer by reducing the suppressive activity of MDSC, polarizing myeloid cells into a M1-like state and recruiting DC. We postulate that tumor cell-targeting combination strategies may benefit from RLH-based TME remodeling. In addition, we provide novel insights into the dual role of IFN signaling in MDSC's suppressive function and provide evidence that host-intrinsic IFN signaling may be critical for MDSC to gain suppressive function during tumor development.