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Senescence-associated secretory proteins induced in lung adenocarcinoma by extended treatment with dexamethasone enhance migration and activation of lymphocytes


There is a need to improve response rates of immunotherapies in lung adenocarcinoma (AC). Extended (7–14 days) treatment of high glucocorticoid receptor (GR) expressing lung AC cells with dexamethasone (Dex) induces an irreversible senescence phenotype through chronic induction of p27. As the senescence-associated secretory phenotype (SASP) may have either tumor supporting or antitumor immunomodulatory effects, it was interest to examine the effects of Dex-induced senescence of lung AC cells on immune cells. Dex-induced senescence resulted in sustained production of CCL2, CCL4, CXCL1 and CXCL2, both in vitro and in vivo. After Dex withdrawal, secretion of these chemokines by the senescent cells attracted peripheral blood monocytes, T-cells, and NK cells. Following treatment with Dex-induced SASP protein(s), the peripheral blood lymphocytes exhibited higher cell count and tumor cytolytic activity along with enhanced Ki67 and perforin expression in T and NK cells. This cytolytic activity was partially attributed to NKG2D, which was upregulated in NK cells by SASP while its ligand MICA/B was upregulated in the senescent cells. Enhanced infiltrations of T and NK cells were observed in human lung AC xenografts in humanized NSG mice, following treatment with Dex. The findings substantiate the idea that induction of irreversible senescence in high-GR expressing subpopulations of lung AC tumors using Dex pretreatment enhances tumor immune infiltration and may subsequently improve the clinical outcome of current immunotherapies.

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  1. Siegel RL, Miller KD, Fuchs HE, Jemal A (2022) Cancer statistics, 2022. CA Cancer J Clin 72:7–33.

    Article  PubMed  Google Scholar 

  2. Reck M, Rodriguez-Abreu D, Robinson AG et al (2019) Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol 37:537–546.

    Article  CAS  PubMed  Google Scholar 

  3. Reck M, Remon J, Hellmann MD (2022) First-line immunotherapy for non-small-cell lung cancer. J Clin Oncol 40:586–597.

    Article  CAS  PubMed  Google Scholar 

  4. Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445:656–660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lasry A, Ben-Neriah Y (2015) Senescence-associated inflammatory responses: aging and cancer perspectives. Trends Immunol 36:217–228.

    Article  CAS  PubMed  Google Scholar 

  6. McHugh CI, Thipparthi MR, Lawhorn-Crews JM et al (2018) Using radiolabeled 3’-Deoxy-3’-(18)F-fluorothymidine with PET to monitor the effect of dexamethasone on non-small cell lung cancer. J Nucl Med 59:1544–1550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Patki M, Gadgeel S, Huang Y, McFall T, Shields AF, Matherly LH, Bepler G, Ratnam M (2014) Glucocorticoid receptor status is a principal determinant of variability in the sensitivity of non-small-cell lung cancer cells to pemetrexed. J Thorac Oncol 9:519–526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Patki M, McFall T, Rosati R et al (2018) Chronic p27(Kip1) induction by dexamethasone causes senescence phenotype and permanent cell cycle blockade in lung adenocarcinoma cells over-expressing glucocorticoid receptor. Sci Rep 8:16006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Parajuli P, Anand R, Mandalaparty C et al (2016) Preferential expression of functional IL-17R in glioma stem cells: potential role in self-renewal. Oncotarget 7:6121–6135.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Paladugu M, Thakur A, Lum LG, Mittal S, Parajuli P (2013) Generation and immunologic functions of Th17 cells in malignant gliomas. Cancer Immunol Immunother 62:75–86.

    Article  CAS  PubMed  Google Scholar 

  11. Griffith JW, Sokol CL, Luster AD (2014) Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev Immunol 32:659–702.

    Article  CAS  PubMed  Google Scholar 

  12. Robertson MJ (2002) Role of chemokines in the biology of natural killer cells. J Leukoc Biol 71:173–183

    Article  CAS  PubMed  Google Scholar 

  13. Rao SG, Jackson JG (2016) SASP: tumor suppressor or promoter? Yes. Trends Cancer 2:676–687.

    Article  PubMed  Google Scholar 

  14. Ruhland MK, Coussens LM, Stewart SA (2016) Senescence and cancer: an evolving inflammatory paradox. Biochim Biophys Acta 1865:14–22.

    Article  CAS  PubMed  Google Scholar 

  15. Velarde MC, Demaria M, Campisi J (2013) Senescent cells and their secretory phenotype as targets for cancer therapy. Interdiscip Top Gerontol 38:17–27.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Franchimont D, Galon J, Vacchio MS et al (2002) Positive effects of glucocorticoids on T cell function by up-regulation of IL-7 receptor alpha. J Immunol 168:2212–2218

    Article  CAS  PubMed  Google Scholar 

  17. Morgan DJ, Davis DM (2017) Distinct effects of dexamethasone on human natural killer cell responses dependent on cytokines. Front Immunol 8:432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Perez SA, Mahaira LG, Demirtzoglou FJ et al (2005) A potential role for hydrocortisone in the positive regulation of IL-15-activated NK-cell proliferation and survival. Blood 106:158–166.

    Article  CAS  PubMed  Google Scholar 

  19. Moustaki A, Argyropoulos KV, Baxevanis CN, Papamichail M, Perez SA (2011) Effect of the simultaneous administration of glucocorticoids and IL-15 on human NK cell phenotype, proliferation and function. Cancer Immunol Immunother 60:1683–1695.

    Article  CAS  PubMed  Google Scholar 

  20. Li Y, He F, Liu S, Zhang Y, Li L, Wang B, Lan L, Pan Z (2021) Effect of pretreatment with dexamethasone on the efficacy and immune-related adverse events of immunotherapy in first-line treatment for advanced non-small cell lung cancer: a network meta-analysis of randomized control trials. Am J Clin Exp Immunol 10:93–102

    PubMed  PubMed Central  Google Scholar 

  21. Wabnitz GH, Michalke F, Stober C, Kirchgessner H, Jahraus B, van den Boomen DJ, Samstag Y (2011) L-plastin phosphorylation: a novel target for the immunosuppressive drug dexamethasone in primary human T cells. Eur J Immunol 41:3157–3169.

    Article  CAS  PubMed  Google Scholar 

  22. Waltzer WC, Bachvaroff RJ, Arnold A, Anaise D, Rapaport FT (1985) Immunological consequence of renal transplantation and immunosuppression: I—alterations in human natural killer-cell activity. J Clin Immunol 5:78–83

    Article  CAS  PubMed  Google Scholar 

  23. Hepburn B, Slade JD (1987) Effect of divided daily dose prednisone therapy on circulating T cell subsets. J Rheumatol 14:19–22

    CAS  PubMed  Google Scholar 

  24. Kiuchi Z, Nishibori Y, Kutsuna S et al (2019) GLCCI1 is a novel protector against glucocorticoid-induced apoptosis in T cells. FASEB J 33:7387–7402.

    Article  CAS  PubMed  Google Scholar 

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Our institutional Microscopy, Imaging and Cytometry Resources (MICR) core facility were used for the flow cytometry studies. The Core is supported, in part, by NIH Center Grant P30 CA22453 to the Karmanos Cancer Institute, Wayne State University, and the Perinatology Research Branch of the National Institutes of Child Health and Development. We are thankful to Jeremy M. Kelm for thorough evaluation of the manuscript for language and grammar.


This study was partially supported by a donation to the Parajuli Lab from Marvin Klein Trust, Michigan.

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PP, NG and MR conceptualized the study, analyzed data and wrote the manuscript; RR performed in vitro and in vivo (SCID mice model) senescence induction studies; SD, LP and NG helped with the in vivo (NSG mice model) studies; HM helped with study design, data analysis and interpretation; REW, ZH, and AN performed all cell culture, migration and cytotoxicity experiments, prepared Figures and wrote Methods.

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Correspondence to Prahlad Parajuli.

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Parajuli, P., Rosati, R., Mamdani, H. et al. Senescence-associated secretory proteins induced in lung adenocarcinoma by extended treatment with dexamethasone enhance migration and activation of lymphocytes. Cancer Immunol Immunother (2022).

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  • Tumor senescence
  • Glucocorticoid receptor
  • Lung adenocarcinoma
  • Chemokines
  • NKG2D
  • Humanized NSG mice