Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

The cytotoxicity of γδT cells in non-small cell lung cancer mediated via coordination of the BCL-2 and AKT pathways

Oncogene volume 42, pages 3648–3654 (2023)Cite this article

Subjects

Abstract

The effectiveness and mechanisms of γδT-cell immunotherapy in lung cancer remain unclear. In this study, we assessed the effects of continuous, low-dose γδT-cell intervention on lung cancer cells. We cultured γδT cells with a lung cancer cell line (A549) and replaced the γδT-cell population every 48 hours. The killing effect of γδTcells on A549 cells and the Half-maximal inhibitory concentration (IC50) value were detected by the cholecystokinin octapeptide (CCK-8) method. The levels of perforin, granzyme B and the inflammatory factors interleukin-6 (IL-6), interferon (IFN)-γ, and tumor necrosis factor-alpha (TNF-a), in the supernatants of cocultured cells were measured by ELISA. The protein expression of Bcl-2, Bax, PI3K and Akt was detected by western blotting. Our results indicated that γδT-cell treatment decreased the protein expression of Bcl-2, PI3K, and AKT but upregulated that of Bax. Moreover, γδT-cell treatment increased perforin and granzyme B release related to the Bax/Bcl-2 signaling pathway. In addition, γδT-cell-mediated cytolysis for A549 cells involved the PI3K/AKT pathway. In vivo results were consistent with the in vitro results. γδT-cell immunotherapy integrated regulation of a signaling pathway network involving the mutual regulation of apoptosis and proliferation. γδT-cell immunotherapy could be used to enhance the cytotoxic killing of lung cancer cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Phenotype of expanded γδT cells.
Fig. 2: Cytotoxicity of γδT cells to A549 cells.
Fig. 3: Antitumor effect of adoptive γδT-cell treatment in vivo.

Similar content being viewed by others

Data availability

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

References

  1. Howlader N, Forjaz G, Mooradian MJ, Meza R, Kong CY, Cronin KA, et al. The Effect of Advances in Lung-Cancer Treatment on Population Mortality. N Engl J Med. 2020;383:640–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  3. Mamdani H, Matosevic S, Khalid AB, Durm G, Jalal SI. Immunotherapy in Lung Cancer: Current Landscape and Future Directions. Front Immunol. 2022;13:823618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Alnaggar M, Xu Y, Li J, He J, Chen J, Li M, et al. Allogenic V9V2 T cell as new potential immunotherapy drug for solid tumor: a case study for cholangiocarcinoma. J Immunother Cancer. 2019;7:36.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Lo Presti E, Pizzolato G, Gulotta E, Cocorullo G, Gulotta G, Dieli F, et al. Current advances in gammadelta T cell-based tumor immunotherapy. Front Immunol. 2017;8:1401.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Silva-Santos B, Mensurado S, Coffelt SB. gammadelta T cells: pleiotropic immune effectors with therapeutic potential in cancer. Nat Rev Cancer. 2019;19:392–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sebestyen Z, Prinz I, Déchanet-Merville J, Silva-Santos B, Kuball J. Translating gammadelta (gammadelta) T cells and their receptors into cancer cell therapies. Nat Rev Drug Discov. 2020;19:169–84.

    Article  CAS  PubMed  Google Scholar 

  8. Kabelitz D, Serrano R, Kouakanou L, Peters C, Kalyan S. Cancer immunotherapy with γδT cells: many paths ahead of us. Cell Mol Immunol. 2020;17:925–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Baugh R, Khalique H, Seymour LW. Convergent Evolution by Cancer and Viruses in Evading the NKG2D Immune Response. Cancers. 2020;12:3827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lai AY, Patel A, Brewer F, Evans K, Johannes K, González LE, et al. Cutting Edge: Bispecific γδT Cell Engager Containing Heterodimeric BTN2A1 and BTN3A1 Promotes Targeted Activation of Vγ9Vδ2+ T Cells in the Presence of Costimulation by CD28 or NKG2D. J Immunol. 2022;209:1475–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Aoki T, Matsushita H, Hoshikawa M, Hasegawa K, Kokudo N, Kakimi K. Adjuvant combination therapy with gemcitabine and autologous gammadelta T-cell transfer in patients with curatively resected pancreatic cancer. Cytotherapy. 2017;19:473–85.

    Article  CAS  PubMed  Google Scholar 

  12. Xu Y, Xiang Z, Alnaggar M, Kouakanou L, Li J, He J, et al. Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer. Cell Mol Immunol. 2021;18:427–39.

    Article  CAS  PubMed  Google Scholar 

  13. Morris EC, Neelapu SS, Giavridis T, Sadelain M. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat Rev Immunol. 2022;22:85–96.

    Article  CAS  PubMed  Google Scholar 

  14. Wang H, Chen H, Liu S, Zhang J, Lu H, Somasundaram R, et al. Costimulation of γδTCR and TLR7/8 promotes Vδ2 T-cell antitumor activity by modulating mTOR pathway and APC function. J Immunother Cancer. 2021;9:e003339.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Zhang Z, Yang C, Li L, Zhu Y, Su K, Zhai L, et al. “γδT Cell-IL17A-Neutrophil” Axis Drives Immunosuppression and Confers Breast Cancer Resistance to High-Dose Anti-VEGFR2 Therapy. Front Immunol. 2021;12:699478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Xie H, Yao J, Wang Y, Ni B. Exosome-transmitted circVMP1 facilitates the progression and cisplatin resistance of non-small cell lung cancer by targeting miR-524-5p-METTL3/SOX2 axis. Drug Deliv. 2022;29:1257–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lu H, Shi T, Wang M, Li X, Gu Y, Zhang X, et al. B7-H3 inhibits the IFN-γ-dependent cytotoxicity of Vγ9Vδ2 T cells against colon cancer cells. Oncoimmunology. 2020;9:1748991.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Chen SJ, Wang SC, Chen YC. The Immunotherapy for Colorectal Cancer, Lung Cancer and Pancreatic Cancer. Int J Mol Sci. 2021;22:12836.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Song Y, Liu Y, Teo HY, Liu H. Targeting Cytokine Signals to Enhance γδT Cell-Based Cancer Immunotherapy. Front Immunol. 2022;13:914839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Barisa M, Fowler D, Fisher J. Interplay between T-Cell Metabolism and Tumour Microenvironment Offers Opportunities for Therapeutic Intervention. Immunometabolism. 2021;3:210026.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kroschinsky F, Stolzel F, von Bonin S, Beutel G, Kochanek M, Kiehl M, et al. New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management. Crit Care. 2017;21:89.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Gong WJ, Qiu Y, Li MH, Chen LY, Li YY, Yu JQ, et al. Investigation of the risk factors to predict cytokine release syndrome in relapsed or refractory B-cell acute lymphoblastic leukemia patients receiving IL-6 knocking down anti-CD19 chimeric antigen receptor T-cell therapy. Front Immunol. 2022;13:922212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sun Y, Hu B, Stanley G, Harris ZM, Gautam S, Homer R, et al. IFN-γ Is Protective in Cytokine Release Syndrome-associated Extrapulmonary Acute Lung Injury. Am J Respir Cell Mol Biol. 2023;68:75–89.

    Article  CAS  PubMed  Google Scholar 

  24. Kim JS, Lee JY, Yang JW, Lee KH, Effenberger M, Szpirt W, et al. Immunopathogenesis and treatment of cytokine storm in COVID-19. Theranostics. 2021;11:316–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Velotti F, Barchetta I, Cimini FA, Cavallo MG. Granzyme B in Inflammatory Diseases: Apoptosis, Inflammation, Extracellular Matrix Remodeling, Epithelial-to-Mesenchymal Transition and Fibrosis. Front Immunol. 2020;11:587581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hoxhaj G, Manning BD. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer. 2020;20:74–88.

    Article  CAS  PubMed  Google Scholar 

  27. Park JH, Pyun WY, Park HW. Cancer Metabolism: Phenotype, Signaling and Therapeutic Targets. Cells. 2020;9:2308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li X, Lu H, Gu Y, Zhang X, Zhang G, Shi T, et al. Tim-3 suppresses the killing effect of Vγ9Vδ2 T cells on colon cancer cells by reducing perforin and granzyme B expression. Exp Cell Res. 2020;386:111719.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study is supported by The Key Research and Development Program of Guangxi (No. GUIKEAB1850004) and the Science and Technology Development Plan Project of Jilin Province (No. 20210204157YY).

Author information

Authors and Affiliations

  1. Department of Endocrinology, Affiliated Hospital of Youjiang Medical University for Nationalities, No. 18 Zhongshan 2 Road, Youjiang District, 533000, Baise City, Guangxi Province, China

    Ying Liu, Qing Huang & Caiyan Yang

  2. Guangxi database construction and application engineering research center for intracorporal pharmacochemistry of TCM, Youjiang medical university for nationalities, No. 2 Chengxiang Road, Youjiang District, 533000, Baise City, Guangxi Province, China

    Tianqi Zhang

  3. Department of Anesthesiology, Affiliated Hospital of Youjiang Medical University for Nationalities, No. 18 Zhongshan 2 Road, Youjiang District, 533000, Baise City, Guangxi Province, China

    Jun Deng

  4. Department of Vascular Surgery, the First Affiliated Hospital of Jilin University, No. 1 Xinmin Street, 130021, Changchun, Jilin Province, China

    Zhihua Cheng

Authors
  1. Ying Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tianqi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jun Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qing Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Caiyan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhihua Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TZ and JD conceived and designed the study and drafted the manuscript. ZC and QH collected, analyzed and interpreted the experimental data. YL and CY revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ying Liu or Zhihua Cheng.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of the Affiliated Hospital of Youjiang Medical University for Nationalities.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Y., Zhang, T., Deng, J. et al. The cytotoxicity of γδT cells in non-small cell lung cancer mediated via coordination of the BCL-2 and AKT pathways. Oncogene 42, 3648–3654 (2023). https://doi.org/10.1038/s41388-023-02852-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-023-02852-x

Search

Advanced search

Quick links