Abstract
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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Acknowledgements
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.
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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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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 72, 1273–1284 (2023). https://doi.org/10.1007/s00262-022-03332-z
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DOI: https://doi.org/10.1007/s00262-022-03332-z