IL20RA signaling enhances stemness and promotes the formation of an immunosuppressive microenvironment in breast cancer.
IL20RA signaling enhances stemness and promotes the formation of an immunosuppressive microenvironment in breast cancer.
复制标题
IL20RA 信号传导增强乳腺癌的干性并促进免疫抑制微环境的形成。
作者：
Gao W;Wen H;Liang L;Dong X;Du R;Zhou W;Zhang X;Zhang C;Xiang R;Li N
原理：肿瘤微环境与肿瘤细胞相互作用，通过各种细胞因子和细胞因子受体调节肿瘤细胞的干性。先前的研究揭示了白细胞介素20受体α亚基（IL 20 RA）信号传导在多种类型肿瘤的进展中可能发挥的作用。然而，它对乳腺癌的干性和微环境的调节作用需要研究。研究方法：采用免疫组织化学染色和Western blot分析方法，研究IL 20 RA和SOX 2在乳腺癌组织和癌旁组织中的表达。酶联免疫吸附试验和TCGA数据集分析进行，以确定IL 20 RA信号转导在乳腺癌进展中的功能。进行功能获得和功能丧失方法以检查IL 20 RA对乳腺癌细胞的干细胞性的影响。通过检测核心干性基因的表达、侧群（SP）、球形形成能力和乙醛脱氢酶（ALDH）活性，分析干性特征。采用流式细胞术检测小鼠肿瘤组织中肿瘤浸润淋巴细胞的变化。基于本研究阐明的相关分子机制，合成了一种新型的IL 20 RA靶向脂质体纳米粒，其包裹信号转导和转录激活因子3（STAT 3）抑制剂stattic（NP-Stattic-IL 20 RA）。将这些纳米颗粒与抗程序性死亡配体1（PD-L1）抗体和化疗药物组合，以抑制小鼠乳腺肿瘤的发展。结果：IL 20 RA在乳腺癌组织中呈高表达，且与SOX 2的表达呈正相关。IL 20 RA增加乳腺癌细胞的SP和ALDHbr比例，增强球体形成能力，并促进核心干性基因如Sox 2和Oct 4的表达，以及增加乳腺癌细胞的化学抗性。IL 20 RA在体内促进乳腺癌细胞的肿瘤起始能力和肺转移。此外，IL 20 RA激活Janus激酶1（JAK 1）-STAT 3-SOX 2信号通路，导致PD-L1表达增加和抗癌淋巴细胞（包括CD 8 + T细胞和自然杀伤细胞）募集减少。同时，IL 20 RA信号增强骨髓源性抑制细胞的比例。与抗PD-L1抗体和NPs-Stattic-IL 20 RA联合使用，在体内乳腺癌小鼠模型中的化疗疗效增加。结论：总的来说，我们的研究结果表明，IL 20 RA通路是一种新的信号通路，参与促进乳腺癌的干细胞特征沿着肿瘤有利的免疫微环境的形成。用STAT 3信号传导抑制与抗PD-L1抗体组合靶向IL 20 RAhi群体可以增加化疗剂对乳腺癌的治疗功效。因此，这项研究为乳腺癌治疗引入了一种有前途的新策略。
Rationale: Tumor microenvironment interacts with tumor cells to regulate their stemness properties through various cytokines and cytokine receptors. Previous studies revealed the possible role of interleukin 20 receptor subunit alpha (IL20RA) signaling in the progression of several types of tumors. However, its regulatory effects on the stemness and the microenvironment of breast cancer need to be studied. Methods: Immunohistochemical staining and western blot analysis were used to evaluate the association between IL20RA and SOX2 in breast tumors and noncancerous tissues. Enzyme-linked immunosorbent assay and TCGA dataset analysis were performed to determine the function of IL20RA signaling in breast cancer progression. Gain- and loss-of-function methods were performed to examine the effects of IL20RA on the stemness of breast cancer cells. The stemness features were analyzed by detecting the expression of core stemness genes, side population (SP), sphere formation ability, and aldehyde dehydrogenase (ALDH) activity. Flow cytometric analysis was applied to detect the changes of tumor-infiltration lymphocytes in tumor tissues in mice. Based on the relevant molecular mechanisms elucidated in this study, a novel IL20RA-targeted liposomal nanoparticle encapsulating the signal transducer and activator of transcription 3 (STAT3) inhibitor stattic (NP-Stattic-IL20RA) was synthesized. These NPs were combined with anti-programmed death ligand 1 (PD-L1) antibody and chemotherapy to inhibit the development of breast tumors in mice. Results: IL20RA is highly expressed in human breast cancers and is positively associated with the SOX2 expression. IL20RA increases the SP and ALDHbr proportions of breast cancer cells, enhances the sphere formation ability, and promotes the expression of core stemness genes, such as Sox2 and Oct4, as well as increases chemoresistance of breast cancer cells. IL20RA promotes the tumor-initiating ability and lung metastasis of breast cancer cells in vivo. In addition, IL20RA activates the Janus kinase 1 (JAK1)-STAT3-SOX2 signaling pathway, leading to increased expression of PD-L1 and reduced recruitment of anti-cancer lymphocytes, including CD8+ T cells and natural killer cells. Meanwhile, IL20RA signaling enhances the proportion of myeloid-derived suppressor cells. Combined with anti-PD-L1 antibody and NPs-Stattic-IL20RA, the chemotherapeutic efficacy was increased in breast cancer mouse models in vivo. Conclusion: Collectively, our results reveal that the IL20RA pathway is a novel signaling pathway involved in promoting the stemness features of breast cancer along with the formation of a tumor-favorable immune microenvironment. Targeting the IL20RAhi population with STAT3 signaling inhibition combined with anti-PD-L1 antibody can increase the therapeutic efficacy of chemotherapeutic agents for breast cancer. This study thus introduces a promising novel strategy for breast cancer therapy.
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影响因子：
7.3
作者：
Kragstrup TW;Andersen T;Heftdal LD;Hvid M;Gerwien J;Sivakumar P;Taylor PC;Senolt L;Deleuran B
通讯作者：
Deleuran B
影响因子：
2.1
作者：
Kragstrup, T. W.
通讯作者：
Kragstrup, T. W.
影响因子：
8.7
作者：
Nurieva RI;Liu X;Dong C
通讯作者：
Dong C
影响因子：
11.5
作者：
Hsing, Chung-Hsi;Cheng, Hung-Chi;Chang, Ming-Shi
通讯作者：
Chang, Ming-Shi
影响因子：
11.2
作者：
Ding ZC;Lu X;Yu M;Lemos H;Huang L;Chandler P;Liu K;Walters M;Krasinski A;Mack M;Blazar BR;Mellor AL;Munn DH;Zhou G
通讯作者：
Zhou G