Department of Geriatrics, The Third Affiliated Hospital of Suzhou University, Changzhou, 213003, Jiangsu, China.
Department of Tumor Biological Treatment, The Third Affiliated Hospital of Suzhou University, Changzhou, 213003, Jiangsu, China.
Med Oncol. 2023 Aug 31;40(10):285. doi: 10.1007/s12032-023-02156-w.
PD-L1 is expressed on antigen-presenting cells and tumor cells, thus allows tumor cells to escape immune surveillance. Moreover, targeting PD-L1 was also recommended and selected as important immune checkpoint inhibitors (ICIs) strategy in the treatment of advanced cancers due to the safety and activity. However, the detailed alteration of tumor microenvironment (TME) upon anti-PD-L1 therapy in lung cancer tumor model still needs to be resolved. In our present study, first, we characterized PD-L1 expression in human lung adenocarcinoma tissues by using public data, then we established the subcutaneous tumor-bearing model by using murine lung cancer cell line 3LL to perform the anti-PD-L1 therapy and the single-cell RNA sequencing (scRNA-seq) to reveal the remodeling of TME. We confirmed that PD-L1 blockade significantly inhibited tumor progression in 3LL mouse lung cancer model. The scRNA-seq depicted the detailed TME landscape of 3LL tumor model upon anti-PD-L1 treatment. Five major populations according to the marker genes were identified, including tumor cells, stromal cells, myeloid cells, T cells, and NK cells. In addition, we found that anti-PD-L1 treatment enhanced tumor immunogenicity and promoted inflammation in TME and promoted cancer-associated fibroblasts (CAFs)-mediated T-cell migration and infiltration. We also found that anti-PD-L1 treatment can increase dendritic cells (DCs) population and enhance the antigen-presenting ability to CD8T cells and promote the transition of monocytes to macrophages and tumor-associated macrophages 2 (TAM2) to TAM1. We also revealed that Nfatc1 was up-regulated in the anti-PD-L1 treatment group, the frequencies of effector CD8T cells, exhausted CD8T cells, cycling T cells, and NKT were increased, and the frequencies of conventional CD4T cells, Treg, IFN-induced T cells, and γδT cells were decreased. Therefore, our scRNA-seq data of the lung cancer tumor model upon anti-PD-L1 treatment made a comprehensive presentation and description about the remodeling of TME and will benefit us to understand the underlying mechanisms and to design combinational therapeutic strategies based on anti-PD-L1 therapy against lung cancer.
PD-L1 表达于抗原呈递细胞和肿瘤细胞上，从而使肿瘤细胞逃避免疫监视。此外，由于安全性和活性，靶向 PD-L1 也被推荐并选择作为晚期癌症治疗的重要免疫检查点抑制剂（ICI）策略。然而，在肺癌肿瘤模型中，抗 PD-L1 治疗后肿瘤微环境（TME）的详细变化仍需要解决。在本研究中，我们首先使用公共数据对人类肺腺癌组织中的 PD-L1 表达进行了表征，然后使用鼠肺癌细胞系 3LL 建立了皮下荷瘤模型，进行抗 PD-L1 治疗和单细胞 RNA 测序（scRNA-seq），以揭示 TME 的重塑。我们证实 PD-L1 阻断显著抑制了 3LL 小鼠肺癌模型中的肿瘤进展。scRNA-seq 描绘了抗 PD-L1 治疗后 3LL 肿瘤模型的详细 TME 景观。根据标记基因，鉴定了包括肿瘤细胞、基质细胞、髓样细胞、T 细胞和 NK 细胞在内的 5 个主要群体。此外，我们发现抗 PD-L1 治疗增强了 TME 中的肿瘤免疫原性并促进了炎症，促进了癌症相关成纤维细胞（CAFs）介导的 T 细胞迁移和浸润。我们还发现，抗 PD-L1 治疗可以增加树突状细胞（DC）群体，增强 CD8T 细胞的抗原呈递能力，并促进单核细胞向巨噬细胞和肿瘤相关巨噬细胞 2（TAM2）向 TAM1 的转化。我们还揭示，在抗 PD-L1 治疗组中 Nfatc1 上调，效应性 CD8T 细胞、耗竭性 CD8T 细胞、循环 T 细胞和 NKT 的频率增加，而常规 CD4T 细胞、Treg、IFN 诱导的 T 细胞和 γδT 细胞的频率降低。因此，我们对抗 PD-L1 治疗后肺癌肿瘤模型的 scRNA-seq 数据进行了全面的呈现和描述，这将有助于我们理解潜在的机制，并基于抗 PD-L1 治疗设计针对肺癌的联合治疗策略。
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