Single-cell RNA sequencing reveals enhanced antitumor immunity after combined application of PD-1 inhibitor and Shenmai injection in non-small cell lung cancer
Abstract Background Immune checkpoint inhibitors (ICIs) have altered the clinical management of non-small cell lung cancer (NSCLC). However, the low response rate, severe immune-related adverse events (irAEs), and hyperprogressive disease following ICIs monotherapy require attention. Combination the...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-023-01184-3 |
| _version_ | 1797778800200646656 |
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| author | Dingyi Yu Penghui Yang Xiaoyan Lu Shaoze Huang Li Liu Xiaohui Fan |
| author_facet | Dingyi Yu Penghui Yang Xiaoyan Lu Shaoze Huang Li Liu Xiaohui Fan |
| author_sort | Dingyi Yu |
| collection | DOAJ |
| description | Abstract Background Immune checkpoint inhibitors (ICIs) have altered the clinical management of non-small cell lung cancer (NSCLC). However, the low response rate, severe immune-related adverse events (irAEs), and hyperprogressive disease following ICIs monotherapy require attention. Combination therapy may overcome these limitations and traditional Chinese medicine with immunomodulatory effects provides a promising approach. Shenmai injection (SMI) is a clinically effective adjuvant treatment for cancer with chemotherapy and radiotherapy. Therefore, the combined effects and mechanisms of SMI and programmed death-1 (PD-1) inhibitor against NSCLC was focused on this study. Methods A Lewis lung carcinoma mouse model and a lung squamous cell carcinoma humanized mouse model were used to investigate the combined efficacy and safety of SMI and PD-1 inhibitor. The synergistic mechanisms of the combination therapy against NSCLC were explored using single-cell RNA sequencing. Validation experiments were performed using immunofluorescence analysis, in vitro experiment, and bulk transcriptomic datasets. Results In both models, combination therapy alleviated tumor growth and prolonged survival without increasing irAEs. The GZMA high and XCL1 high natural killer (NK) cell subclusters with cytotoxic and chemokine signatures increased in the combination therapy, while malignant cells from combination therapy were mainly in the apoptotic state, suggesting that mediating tumor cell apoptosis through NK cells is the main synergistic mechanisms of combination therapy. In vitro experiment confirmed that combination therapy increased secretion of Granzyme A by NK cells. Moreover, we discovered that PD-1 inhibitor and SMI combination blocked inhibitory receptors on NK and T cells and restores their antitumoral activity in NSCLC better than PD-1 inhibitor monotherapy, and immune and stromal cells exhibited a decrease of angiogenic features and attenuated cancer metabolism reprogramming in microenvironment of combination therapy. Conclusions This study demonstrated that SMI reprograms tumor immune microenvironment mainly by inducing NK cells infiltration and synergizes with PD-1 inhibitor against NSCLC, suggested that targeting NK cells may be an important strategy for combining with ICIs. Video Abstract |
| first_indexed | 2024-03-12T23:22:47Z |
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| id | doaj.art-e905b9db5b1c4c9d8a932c3c6b161998 |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-03-12T23:22:47Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-e905b9db5b1c4c9d8a932c3c6b1619982023-07-16T11:23:04ZengBMCCell Communication and Signaling1478-811X2023-07-0121112610.1186/s12964-023-01184-3Single-cell RNA sequencing reveals enhanced antitumor immunity after combined application of PD-1 inhibitor and Shenmai injection in non-small cell lung cancerDingyi Yu0Penghui Yang1Xiaoyan Lu2Shaoze Huang3Li Liu4Xiaohui Fan5Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang UniversityPharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang UniversityPharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang UniversityZhejiang Engineering Research Center for Advanced Manufacturing of Traditional Chinese MedicineZhejiang Engineering Research Center for Advanced Manufacturing of Traditional Chinese MedicinePharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang UniversityAbstract Background Immune checkpoint inhibitors (ICIs) have altered the clinical management of non-small cell lung cancer (NSCLC). However, the low response rate, severe immune-related adverse events (irAEs), and hyperprogressive disease following ICIs monotherapy require attention. Combination therapy may overcome these limitations and traditional Chinese medicine with immunomodulatory effects provides a promising approach. Shenmai injection (SMI) is a clinically effective adjuvant treatment for cancer with chemotherapy and radiotherapy. Therefore, the combined effects and mechanisms of SMI and programmed death-1 (PD-1) inhibitor against NSCLC was focused on this study. Methods A Lewis lung carcinoma mouse model and a lung squamous cell carcinoma humanized mouse model were used to investigate the combined efficacy and safety of SMI and PD-1 inhibitor. The synergistic mechanisms of the combination therapy against NSCLC were explored using single-cell RNA sequencing. Validation experiments were performed using immunofluorescence analysis, in vitro experiment, and bulk transcriptomic datasets. Results In both models, combination therapy alleviated tumor growth and prolonged survival without increasing irAEs. The GZMA high and XCL1 high natural killer (NK) cell subclusters with cytotoxic and chemokine signatures increased in the combination therapy, while malignant cells from combination therapy were mainly in the apoptotic state, suggesting that mediating tumor cell apoptosis through NK cells is the main synergistic mechanisms of combination therapy. In vitro experiment confirmed that combination therapy increased secretion of Granzyme A by NK cells. Moreover, we discovered that PD-1 inhibitor and SMI combination blocked inhibitory receptors on NK and T cells and restores their antitumoral activity in NSCLC better than PD-1 inhibitor monotherapy, and immune and stromal cells exhibited a decrease of angiogenic features and attenuated cancer metabolism reprogramming in microenvironment of combination therapy. Conclusions This study demonstrated that SMI reprograms tumor immune microenvironment mainly by inducing NK cells infiltration and synergizes with PD-1 inhibitor against NSCLC, suggested that targeting NK cells may be an important strategy for combining with ICIs. Video Abstracthttps://doi.org/10.1186/s12964-023-01184-3Non-small cell lung cancerSingle-cell RNA sequencingProgrammed death-1 inhibitorShenmai injectionNatural killer cells |
| spellingShingle | Dingyi Yu Penghui Yang Xiaoyan Lu Shaoze Huang Li Liu Xiaohui Fan Single-cell RNA sequencing reveals enhanced antitumor immunity after combined application of PD-1 inhibitor and Shenmai injection in non-small cell lung cancer Cell Communication and Signaling Non-small cell lung cancer Single-cell RNA sequencing Programmed death-1 inhibitor Shenmai injection Natural killer cells |
| title | Single-cell RNA sequencing reveals enhanced antitumor immunity after combined application of PD-1 inhibitor and Shenmai injection in non-small cell lung cancer |
| title_full | Single-cell RNA sequencing reveals enhanced antitumor immunity after combined application of PD-1 inhibitor and Shenmai injection in non-small cell lung cancer |
| title_fullStr | Single-cell RNA sequencing reveals enhanced antitumor immunity after combined application of PD-1 inhibitor and Shenmai injection in non-small cell lung cancer |
| title_full_unstemmed | Single-cell RNA sequencing reveals enhanced antitumor immunity after combined application of PD-1 inhibitor and Shenmai injection in non-small cell lung cancer |
| title_short | Single-cell RNA sequencing reveals enhanced antitumor immunity after combined application of PD-1 inhibitor and Shenmai injection in non-small cell lung cancer |
| title_sort | single cell rna sequencing reveals enhanced antitumor immunity after combined application of pd 1 inhibitor and shenmai injection in non small cell lung cancer |
| topic | Non-small cell lung cancer Single-cell RNA sequencing Programmed death-1 inhibitor Shenmai injection Natural killer cells |
| url | https://doi.org/10.1186/s12964-023-01184-3 |
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