Electroacupuncture combined with cisplatin induces an effective anti-tumor immune response by protecting chemotherapy-impaired bone marrow hematopoiesis in non-small cell lung cancer mice

Abstract

Objective: The effectiveness of chemotherapy is affected by tumor heterogeneity and drug resistance mechanisms; however, there are certain limitations. Electroacupuncture can regulate the tumor immune response and restore bone marrow hematopoietic function, which is affected by chemotherapy. This study investigated the efficacy and mechanism of electroacupuncture combined with cisplatin in the treatment of non-small-cell lung cancer mice.

Methods: To establish a mouse model of non-small-cell lung cancer, gene sequencing combined with bioinformatics analysis, flow cytometry, and liquid-phase chips was used to observe the expression of immune cells and related factors in the mouse tumor microenvironment. Flow cytometry was used to observe subpopulations of mouse bone marrow hematopoietic stem cells and progenitor cells. PAC1 receptor agonists were used to observe mouse tumor immunity and bone marrow hematopoiesis-related indicators.

Results: The combination of electroacupuncture with high- and low-dose chemotherapy had a better tumor-suppressive effect. Electroacupuncture can affect the gene expression profile of immune cells, especially the expression levels of Ccr1, Cxcr5, Zbp1, and CamkIIα, and increases the levels of interferon-γ (IFN-γ) and interleukin (IL)-2 protein, upregulating the levels of cytokines Ccl4, Ccl3, and IL-6 in the tumor tissue. Additionally, electroacupuncture enhanced the infiltration of CD8⁺ T cells, dendritic cells, and M1-type macrophages at the tumor site, and reduced the proportion of Th17 and Treg cells. Furthermore, electroacupuncture remodels the bone marrow hematopoietic microenvironment after chemotherapy by increasing the number of bone marrow hematopoietic stem cell subsets, leukocytes, and subpopulations in the peripheral blood. PAC1 receptor agonists have similar effects to those of electroacupuncture on hematopoietic protection and tumor immunity after chemotherapy.

Conclusions: Electroacupuncture may improve chemotherapy-induced bone marrow suppression, reshape the tumor microenvironment immune response affected by chemotherapy, and change the tumor immune microenvironment to an anti-tumor mode by regulating tumor local immune-related cytokines. The PAC1 receptor may be a drug target for the treatment of myelosuppression and immunosuppression in patients with tumors.

Keywords

Bone marrow hematopoiesis / Cisplatin / Electroacupuncture / Immune / PACAP / Tumor microenvironment

Conflict of interest statement

The authors declare no conflict of interest.

Funding

This work was supported by the National Key Research and Development Program of China (2022YFC3500404), the Natural Science Foundation of China (NSFC) (81704146, 82205310), the Research Program Project of Tianjin Education Commission (2021KJ120), and the National College Student Innovation and Entrepreneurship Training Program (202410063009).

Author contributions

Zhifang Xu and Yi Guo conceived the project. Jiaqi Wang, Yuanzhen Yang, Shanshan Lu, Jin Huang, Chaoyang Zhang, Hongen Chang, Quynh Vo Dai, and Narendra Lamichhane performed the experiments. Jiaqi Wang, Yuanzhen Yang, Shanshan Li, Suhong Zhao, Shiyu Miao, and Ganlu Sun performed the data analysis. Zhifang Xu, Yi Guo, Kai Du, Xiaohua Wen, Ning Ma provided administrative, technical, or material support. Jiaqi Wang and Yuanzhen Yang analyzed data, organized data presentation, and completed manuscript writing and preparation. Zhifang Xu reviewed and edited. All authors contributed to the article and approved the submitted version.

Ethical approval of studies and informed consent

The experimental procedures were approved by the Tianjin University of Traditional Chinese Medicine Animal Research Committee (TCM-LAEC2019057).

Acknowledgments

None.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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