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Single-cell RNA sequencing reveals the effects of anti-PD-L1 therapy on 3LL lung cancer model and its tumor microenvironment

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Abstract

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 CD8+T 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 CD8+T cells, exhausted CD8+T cells, cycling T cells, and NKT were increased, and the frequencies of conventional CD4+T 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.

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Funding

The present study was supported by the National Natural Science Foundation of China (82172689), the Key R&D Project of Jiangsu Province (BE2022721), the Natural Science Foundation of Jiangsu Province (BK20211065), High-Level Talents Project of Changzhou Health Bureau (KY20221390), the Applied Basic Research Foundation of Changzhou (CJ20210089 and CE20215030), and Changzhou International Cooperation Project (CZ20210035).

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  1. Hongyu Zhang and Hao Huang have contributed equally to this work.

Authors and Affiliations

  1. Department of Geriatrics, The Third Affiliated Hospital of Suzhou University, Changzhou, 213003, Jiangsu, China

    Hongyu Zhang, Xian He & Zhigang Wang

  2. Department of Tumor Biological Treatment, The Third Affiliated Hospital of Suzhou University, Changzhou, 213003, Jiangsu, China

    Hongyu Zhang, Hao Huang, Shaoxian Wu, Xian He, Junjun Chen, Xiao Zheng & Lujun Chen

  3. Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Suzhou University, Changzhou, 213003, China

    Hongyu Zhang, Hao Huang, Shaoxian Wu, Xian He, Junjun Chen, Xiao Zheng & Lujun Chen

  4. Institute of Cell Therapy, The Third Affiliated Hospital of Suzhou University, Changzhou, 213003, Jiangsu, China

    Hongyu Zhang, Hao Huang, Shaoxian Wu, Xian He, Junjun Chen, Xiao Zheng & Lujun Chen

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  1. Hongyu Zhang
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Contributions

LC and ZW designed and supervised the study. HZ, HH, SW, XH, JC, and XZ conducted the experiments. HH and HZ contributed to the analysis of the scRNA-seq data. LC and ZW wrote the manuscript. All the authors read and approved the final manuscript.

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Correspondence to Lujun Chen or Zhigang Wang.

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Zhang, H., Huang, H., Wu, S. et al. Single-cell RNA sequencing reveals the effects of anti-PD-L1 therapy on 3LL lung cancer model and its tumor microenvironment. Med Oncol 40, 285 (2023). https://doi.org/10.1007/s12032-023-02156-w

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