Reshaping the Immune Microenvironment by Oncolytic Herpes Simplex Virus in Murine Pancreatic Ductal Adenocarcinoma
Reshaping the Immune Microenvironment by Oncolytic Herpes Simplex Virus in Murine Pancreatic Ductal Adenocarcinoma
复制标题
溶瘤单纯疱疹病毒重塑小鼠胰管腺癌的免疫微环境。
DOI：
10.1016/j.ymthe.2020.10.027
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发表时间：
2021-02-03
影响因子：
12.4
通讯作者：
Cao, Youjia
中科院分区：
文献类型：
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作者：
Zhang, Liming;Wang, Wei;Cao, Youjia
胰腺导管腺癌（PDAC）是胰腺恶性肿瘤的主要类型，预后非常差。尽管免疫检查点抑制剂（ICIs）在一些实体肿瘤中取得了令人鼓舞的结果，但由于其免疫抑制肿瘤微环境（TME），免疫治疗对PDAC的效果较差。在本报告中，我们建立了免疫活性的同基因PDAC模型，研究了溶瘤性单纯疱疹病毒-1 （oHSV）对TME免疫细胞组成的影响。oHSV治疗可显著降低荷瘤小鼠的肿瘤负荷，延长荷瘤小鼠的生存期。此外，通过单细胞RNA测序（scRNA-seq）和多色荧光活化细胞分选（FACS）分析，我们证明oHSV给药下调肿瘤相关巨噬细胞（tam），特别是抗炎巨噬细胞，并增加肿瘤浸润淋巴细胞的百分比，包括活化的细胞毒性CD8(+) T细胞和T辅助（Th）1细胞。此外，oHSV与免疫检查点调节剂联合使用可延长荷瘤小鼠的寿命。总的来说，我们的数据表明oHSV通过增强免疫活性来重塑PDAC的TME，并导致PDAC对免疫治疗的反应性提高。
Pancreatic ductal adenocarcinoma (PDAC) is the major type of pancreatic malignancy with very poor prognosis. Despite the promising results of immune checkpoint inhibitors (ICIs) in some solid tumors, immunotherapy is less effective for PDAC due to its immunosuppressive tumor microenvironment (TME). In this report, we established an immunocompetent syngeneic PDAC model and investigated the effect of oncolytic herpes simplex virus-1 (oHSV) on the composition of TME immune cells. The oHSV treatment significantly reduced tumor burden and prolonged the survival of tumor-bearing mice. Further, by single cell RNA sequencing (scRNA-seq) and multicolor fluorescence-activated cell sorting (FACS) analysis, we demonstrated that oHSV administration downregulated tumor-associated macrophages (TAMs), especially the anti-inflammatory macrophages, and increased the percentage of tumor-infiltrating lymphocytes, including activated cytotoxic CD8(+) T cells and T helper (Th)1 cells. Besides, the combination of oHSV and immune checkpoint modulators extended the lifespan of the tumor-bearing mice. Overall, our data suggested that oHSV reshapes the TME of PDAC by boosting the immune activity and leads to improved responsiveness of PDAC to immunotherapy.