Department of Immunology and Research Center of Basic Medical Sciences, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, China.
Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China.
J Immunother Cancer. 2020 Jun;8(1). doi: 10.1136/jitc-2019-000253.
Immune checkpoint blockade has emerged as a potential cancer immunotherapy. The "don't eat me" signal in cancer cells binds signal regulatory protein-α on macrophages and prevents their phagocytosis. The role of miR-340 in pancreatic ductal adenocarcinoma (PDAC), especially in tumor immunity, has not been explored. Here, we examined the clinical and biological relevance of miR-340 and the molecular pathways regulated by miR-340 in PDAC.
and miR-340 expression and the relationship with cancer patient survival were analyzed by bioinformatics. The mechanism of miR-340 action was explored through bioinformatics, luciferase reporter, qRT-PCR and western blot analyses. The effects of miR-340 on cancer cells were analyzed in terms of apoptosis, proliferation, migration and phagocytosis by macrophages. tumorigenesis was studied in orthotopic and subcutaneous models, and immune cells from the peripheral and tumor immune microenvironments were analyzed by flow cytometry. Depletion of macrophages was used to verify the role of macrophages in impacting the function of miR-340 in tumor progression.
miR-340 directly regulates and inversely correlates with and it predicts patient survival in PDAC. The restoration of miR-340 expression in pancreatic cancer cells was sufficient to downregulate and promote phagocytosis of macrophages, further inhibiting tumor growth. The overexpression of miR-340 promoted macrophages to become M1-like phenotype polarized in peripheral and tumor immune microenvironments and increased T cells, especially CD8 T cells, contributing to the antitumor effect of miR-340.
miR-340 is a key regulator of phagocytosis and antitumor immunity, and it could offer a new opportunity for immunotherapy for PDAC.
免疫检查点阻断已成为一种有潜力的癌症免疫疗法。癌细胞中的“别吃我”信号与巨噬细胞上的信号调节蛋白-α结合，阻止其吞噬作用。miR-340 在胰腺导管腺癌 (PDAC) 中的作用，特别是在肿瘤免疫方面，尚未得到探索。在这里，我们研究了 miR-340 的临床和生物学相关性以及 miR-340 在 PDAC 中调节的分子途径。
通过生物信息学分析 miR-340 的表达及其与癌症患者生存的关系。通过生物信息学、荧光素酶报告基因、qRT-PCR 和 Western blot 分析探讨了 miR-340 的作用机制。通过分析凋亡、增殖、迁移和巨噬细胞吞噬作用来研究 miR-340 对癌细胞的影响。通过原位和皮下模型研究肿瘤发生，并通过流式细胞术分析外周和肿瘤免疫微环境中的免疫细胞。通过耗尽巨噬细胞来验证巨噬细胞在影响 miR-340 在肿瘤进展中的功能方面的作用。
miR-340 直接调节并与负相关，可预测 PDAC 患者的生存情况。在胰腺癌细胞中恢复 miR-340 的表达足以下调并促进巨噬细胞的吞噬作用，从而进一步抑制肿瘤生长。miR-340 的过表达促进巨噬细胞在外周和肿瘤免疫微环境中向 M1 样表型极化，并增加 T 细胞，特别是 CD8 T 细胞，有助于 miR-340 的抗肿瘤作用。
miR-340 是吞噬作用和抗肿瘤免疫的关键调节因子，为 PDAC 的免疫治疗提供了新的机会。
