https://doi.org/10.4081/ejh.2024.4098
Astragaloside IV augments anti-PD-1 therapy to suppress tumor growth in lung cancer by remodeling the tumor microenvironment
Submitted: 30 June 2024
Accepted: 22 August 2024
Published: 23 October 2024
Accepted: 22 August 2024
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
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Programmed cell death protein-1 (PD-1) inhibitors are increasingly utilized in the treatment of lung cancer (LC). Combination therapy has recently gained popularity in treating LC. This study aimed to assess the efficacy of combining Astragaloside IV (AS-IV) and anti-PD-1 in LC. C57BL/6J mice were subcutaneously injected with Lewis lung carcinoma (LLC) cells. After 3 weeks, the animals were sacrificed, and the tumors were harvested for analysis. Ki-67 immuno-labeling and TUNEL assay were used for evaluating cell proliferation and apoptosis in tumor tissues. In addition, anti-cleaved caspase 3 was used for immunolabelling of apoptotic cells. Immune cell infiltration (macrophages and T cells) and gene expression in tumor tissues were also investigated by using immunofluorescence staining. Compared to treatment with anti-PD-1 or AS-IV, the combination of AS-IV and anti-PD-1 notably reduced tumor volume and weight of LLC-bearing mice. Additionally, the combination treatment strongly induced the apoptosis and suppressed the proliferation in tumor tissues through inactivating PI3K/Akt and ERK signaling pathways, compared to single treatment group. Moreover, the combination treatment elevated levels of the M1 macrophage marker mCD86, reduced levels of the M2 macrophage marker mCD206, as well as upregulated levels of the T cell activation marker mCD69 in tumor tissues. Collectively, the combination treatment effectively inhibited tumor growth in LLC mice through promoting M1 macrophage polarization and T cell activation. These findings showed that combining AS-IV with anti-PD-1 therapy could be a promising therapeutic approach for LC.
Liu Z, Ma L, Sun Y, Yu W, Wang X. Targeting STAT3 signaling overcomes gefitinib resistance in non-small cell lung cancer. Cell Death Dis 2021;12:561.
DOI: https://doi.org/10.1038/s41419-021-03844-z
Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63.
DOI: https://doi.org/10.3322/caac.21834
Zhou G. Tobacco, air pollution, environmental carcinogenesis, and thoughts on conquering strategies of lung cancer. Cancer Biol Med 2019;16:700-13.
DOI: https://doi.org/10.20892/j.issn.2095-3941.2019.0180
Chen S, Qiao Y, Chen J, Li Y, Xie J, Cui P, et al. Evolutions in the management of non-small cell lung cancer: A bibliometric study from the 100 most impactful articles in the field. Front Oncol 2022;12:939838.
DOI: https://doi.org/10.3389/fonc.2022.939838
Zhang N, Shen J, Gou L, Cao M, Ding W, Luo P, et al. UBE3A deletion enhances the efficiency of immunotherapy in non-small-cell lung cancer. Bioengineered 2022;13:11577-92.
DOI: https://doi.org/10.1080/21655979.2022.2069328
Hashimoto K, Nishimura S, Ito T, Akagi M. Characterization of PD-1/PD-L1 immune checkpoint expression in soft tissue sarcomas. Eur J Histochem 2021;65:3203.
DOI: https://doi.org/10.4081/ejh.2021.3203
Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 2007;19:813-24.
DOI: https://doi.org/10.1093/intimm/dxm057
Taki S, Matsuoka K, Nishinaga Y, Takahashi K, Yasui H, Koike C, et al. Spatiotemporal depletion of tumor-associated immune checkpoint PD-L1 with near-infrared photoimmunotherapy promotes antitumor immunity. J Immunother Cancer 2021;9:e003036.
DOI: https://doi.org/10.1136/jitc-2021-003036
Hashimoto K, Nishimura S, Shinyashiki Y, Ito T, Kakinoki R, Akagi M. Clinicopathological assessment of PD-1/PD-L1 immune checkpoint expression in desmoid tumors. Eur J Histochem 2023;67:3688.
DOI: https://doi.org/10.4081/ejh.2023.3688
Lu X, Shen J, Huang S, Liu D, Wang H. Tumor cells-derived exosomal PD-L1 promotes the growth and invasion of lung cancer cells in vitro via mediating macrophages M2 polarization. Eur J Histochem 2023;67:3784.
DOI: https://doi.org/10.4081/ejh.2023.3784
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192:1027-34.
DOI: https://doi.org/10.1084/jem.192.7.1027
Widmaier M, Wiestler T, Walker J, Barker C, Scott ML, Sekhavati F, et al. Comparison of continuous measures across diagnostic PD-L1 assays in non-small cell lung cancer using automated image analysis. Mod Pathol 2020;33:380-90.
DOI: https://doi.org/10.1038/s41379-019-0349-y
Dantoing E, Piton N, Salaün M, Thiberville L, Guisier F. Anti-PD1/PD-L1 immunotherapy for non-small cell lung cancer with actionable oncogenic driver mutations. Int J Mol Sci 2021;22:6288.
DOI: https://doi.org/10.3390/ijms22126288
Alburquerque-Bejar JJ, Navajas-Chocarro P, Saigi M, Ferrero-Andres A, Morillas JM, Vilarrubi A, et al. MYC activation impairs cell-intrinsic IFNγ signaling and confers resistance to anti-PD1/PD-L1 therapy in lung cancer. Cell Rep Med 2023;4:101006.
DOI: https://doi.org/10.1016/j.xcrm.2023.101006
Yu WD, Sun G, Li J, Xu J, Wang X. Mechanisms and therapeutic potentials of cancer immunotherapy in combination with radiotherapy and/or chemotherapy. Cancer Lett 2019;452:66-70.
DOI: https://doi.org/10.1016/j.canlet.2019.02.048
Xu J, Shen J, Gu S, Zhang Y, Wu L, Wu J, et al. Camrelizumab in combination with apatinib in patients with advanced hepatocellular carcinoma (RESCUE): a nonrandomized, open-label, phase II trial. Clin Cancer Res 2021;27:1003-11.
DOI: https://doi.org/10.1158/1078-0432.CCR-20-2571
Chen Y, Zhang F, Du Z, Xie J, Xia L, Hou X, et al. Proteome analysis of Camellia nitidissima Chi revealed its role in colon cancer through the apoptosis and ferroptosis pathway. Front Oncol 2021;11:727130.
DOI: https://doi.org/10.3389/fonc.2021.727130
Tan YQ, Chen HW, Li J. Astragaloside IV: an effective drug for the treatment of cardiovascular diseases. Drug Des Devel Ther 2020;14:3731-46.
DOI: https://doi.org/10.2147/DDDT.S272355
Liang Y, Chen B, Liang D, Quan X, Gu R, Meng Z, et al. Pharmacological effects of astragaloside IV: a review. Molecules 2023;28:6118.
DOI: https://doi.org/10.3390/molecules28166118
Xu F, Cui WQ, Wei Y, Cui J, Qiu J, Hu LL, et al. Astragaloside IV inhibits lung cancer progression and metastasis by modulating macrophage polarization through AMPK signaling. J Exp Clin Cancer Res 2018;37:207.
DOI: https://doi.org/10.1186/s13046-018-0878-0
Kashfi K, Kannikal J, Nath N. Macrophage Reprogramming and cancer therapeutics: role of iNOS-derived NO. Cells 2021;10:3194.
DOI: https://doi.org/10.3390/cells10113194
Guo M, Abd-Rabbo D, Bertol BC, Carew M, Lukhele S, Snell LM, et al. Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control. Cell Rep 2023;42:113047.
DOI: https://doi.org/10.1016/j.celrep.2023.113047
Sasu B, Chaparro-Riggers J. T cell redirecting therapies for cancer treatment. Curr Cancer Drug Targets 2016;16:22-33.
DOI: https://doi.org/10.2174/1568009615666150827093149
Luo Z, Wang Y, Xue M, Xia F, Zhu L, Li Y, et al. Astragaloside IV ameliorates fat metabolism in the liver of ageing mice through targeting mitochondrial activity. J Cell Mol Med 2021;25:8863-76.
DOI: https://doi.org/10.1111/jcmm.16847
Zheng Y, Dai Y, Liu W, Wang N, Cai Y, Wang S, et al. Astragaloside IV enhances taxol chemosensitivity of breast cancer via caveolin-1-targeting oxidant damage. J Cell Physiol 2019;234:4277-90.
DOI: https://doi.org/10.1002/jcp.27196
Liu J, Chen L, Zhang J, Luo X, Tan Y, Qian S. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy. Open Med (Wars) 2023;18:20230799.
DOI: https://doi.org/10.1515/med-2023-0799
Shen L, Li Y, Hu G, Song X, Wang X, Li X, et al. Astragaloside IV suppresses the migration and EMT progression of cervical cancer cells by inhibiting macrophage M2 polarization through TGFβ/Smad2/3 signaling. Funct Integr Genomics 2023;23:133.
DOI: https://doi.org/10.1007/s10142-023-01017-z
Lai ST, Wang Y, Peng F. Astragaloside IV sensitizes non-small cell lung cancer cells to cisplatin by suppressing endoplasmic reticulum stress and autophagy. J Thorac Dis 2020;12:3715-24.
DOI: https://doi.org/10.21037/jtd-20-2098
Cheng K, Cai N, Zhu J, Yang X, Liang H, Zhang W. Tumor-associated macrophages in liver cancer: From mechanisms to therapy. Cancer Commun (Lond) 2022;42:1112-40.
DOI: https://doi.org/10.1002/cac2.12345
Xia Y, Rao L, Yao H, Wang Z, Ning P, Chen X. Engineering macrophages for cancer immunotherapy and drug delivery. Adv Mater 2020;32:e2002054.
DOI: https://doi.org/10.1002/adma.202002054
Zhang H, Liu L, Liu J, Dang P, Hu S, Yuan W, et al. Roles of tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for solid cancers. Mol Cancer 2023;22:58.
DOI: https://doi.org/10.1186/s12943-023-01725-x
Li Z, Ding Y, Liu J, Wang J, Mo F, Wang Y, et al. Depletion of tumor associated macrophages enhances local and systemic platelet-mediated anti-PD-1 delivery for post-surgery tumor recurrence treatment. Nat Commun 2022;13:1845.
DOI: https://doi.org/10.1038/s41467-022-29388-0
Wei Z, Zhang X, Yong T, Bie N, Zhan G, Li X, et al. Boosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles. Nat Commun 2021;12:440.
DOI: https://doi.org/10.1038/s41467-020-20723-x
Yu Y, Hao J, Wang L, Zheng X, Xie C, Liu H, et al. Astragaloside IV antagonizes the malignant progression of breast cancer induced by macrophage M2 polarization through the TGF-β-regulated Akt/Foxo1 pathway. Pathol Res Pract 2023;249:154766.
DOI: https://doi.org/10.1016/j.prp.2023.154766
Min L, Wang H, Qi H. Astragaloside IV inhibits the progression of liver cancer by modulating macrophage polarization through the TLR4/NF-κB/STAT3 signaling pathway. Am J Transl Res 2022;14:1551-66.
Cheng C, Yi J, Wang R, Cheng L, Wang Z, Lu W. Protection of spleen tissue of γ-ray irradiated mice against immunosuppressive and oxidative effects of radiation by adenosine 5'-monophosphate. Int J Mol Sci 2018;19:1273.
DOI: https://doi.org/10.3390/ijms19051273
Simula L, Pacella I, Colamatteo A, Procaccini C, Cancila V, Bordi M, et al. Drp1 controls effective T cell immune-surveillance by regulating T cell migration, proliferation, and cMyc-dependent metabolic reprogramming. Cell Rep 2018;25:3059-73.e10.
DOI: https://doi.org/10.1016/j.celrep.2018.11.018
Kersten K, Hu KH, Combes AJ, Samad B, Harwin T, Ray A, et al. Spatiotemporal co-dependency between macrophages and exhausted CD8(+) T cells in cancer. Cancer Cell 2022;40:624-38.e9.
DOI: https://doi.org/10.1016/j.ccell.2022.05.004
Li F, Li C, Cai X, Xie Z, Zhou L, Cheng B, et al. The association between CD8+ tumor-infiltrating lymphocytes and the clinical outcome of cancer immunotherapy: A systematic review and meta-analysis. EClinicalMedicine 2021;41:101134.
DOI: https://doi.org/10.1016/j.eclinm.2021.101134
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005;25:9543-53.
DOI: https://doi.org/10.1128/MCB.25.21.9543-9553.2005
Zhang A, Zheng Y, Que Z, Zhang L, Lin S, Le V, et al. Astragaloside IV inhibits progression of lung cancer by mediating immune function of Tregs and CTLs by interfering with IDO. J Cancer Res Clin Oncol 2014;140:1883-90.
DOI: https://doi.org/10.1007/s00432-014-1744-x
Meng Y, Wang W, Chen M, Chen K, Xia X, Zhou S, et al. GBP1 facilitates indoleamine 2,3-dioxygenase extracellular secretion to promote the malignant progression of lung cancer. Front Immunol 2020;11:622467.
DOI: https://doi.org/10.3389/fimmu.2020.622467
Xu JC, Chen TY, Liao LT, Chen T, Li QL, Xu JX, et al. NETO2 promotes esophageal cancer progression by inducing proliferation and metastasis via PI3K/AKT and ERK pathway. Int J Biol Sci 2021;17:259-70.
DOI: https://doi.org/10.7150/ijbs.53795
Zhang Z, Richmond A, Yan C. Immunomodulatory properties of PI3K/AKT/mTOR and MAPK/MEK/ERK inhibition augment response to immune checkpoint blockade in melanoma and triple-negative breast cancer. Int J Mol Sci 2022;23 :7353.
DOI: https://doi.org/10.3390/ijms23137353
Gao L, Yang T, Zhang S, Liang Y, Shi P, Ren H, et al. EHF enhances malignancy by modulating AKT and MAPK/ERK signaling in non‑small cell lung cancer cells. Oncol Rep 2021;45:102.
DOI: https://doi.org/10.3892/or.2021.8053
Ma Y, Li Y, Wu T, Li Y, Wang Q. Astragaloside IV Attenuates programmed death-ligand 1-mediated immunosuppression during liver cancer development via the miR-135b-5p/CNDP1 axis. Cancers (Basel) 2023;15:5048.
DOI: https://doi.org/10.3390/cancers15205048
Li B, Wang F, Liu N, Shen W, Huang T. Astragaloside IV inhibits progression of glioma via blocking MAPK/ERK signaling pathway. Biochem Biophys Res Commun 2017;491:98-103.
DOI: https://doi.org/10.1016/j.bbrc.2017.07.052
Ethics Approval
all animal studies were approved by The First Affiliated Hospital of Hunan University of Traditional Chinese MedicineSupporting Agencies
Key Research Office of Traditional Chinese Medicine Lung DiseaseHow to Cite
Wu, T., Wu, S., Gao, H., Liu, H., Feng, J., & Yin, G. (2024). Astragaloside IV augments anti-PD-1 therapy to suppress tumor growth in lung cancer by remodeling the tumor microenvironment. European Journal of Histochemistry, 68(4). https://doi.org/10.4081/ejh.2024.4098
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