Smadar Gertel, Ari Polachek, Victoria Furer, Tali Ofir Dovrat, Chen Avaky, Adi Broyde, Hila Nochimovitz, Ori Elkayam
{"title":"糖皮质激素联合免疫检查点抑制剂对淋巴细胞活化基因-3和程序性死亡-1表达的缓解作用","authors":"Smadar Gertel, Ari Polachek, Victoria Furer, Tali Ofir Dovrat, Chen Avaky, Adi Broyde, Hila Nochimovitz, Ori Elkayam","doi":"10.1002/eji.70033","DOIUrl":null,"url":null,"abstract":"<p>Cancer immunotherapy with immune checkpoint inhibitors (ICI) shows promising therapeutic efficacy but can cause immune-related adverse events (irAEs). Glucocorticoids (GCs) are commonly employed with ICI to mitigate irAEs. We had found previously that GCs upregulate significantly the inhibitory molecule, lymphocyte activation gene-3 (LAG-3) in peripheral blood and synovial fluid mononuclear cells (PBMCs and SFMCs, respectively). Here, we investigated the effect of GCs combined with ICI on LAG-3 and programmed death-1 (PD-1) expression in SFMCs of 32 inflammatory arthritis patients and PBMCs of 15 healthy controls. GC+Pembrolizumab (PEM, anti-PD-1) induced IL-10 and suppressed IFN-γ, TNF-α, and IL-17A mRNA expressions compared with PEM alone in PBMCs and SFMCs. PBMC proliferation was markedly inhibited by GC+PEM (3.5 ± 0.7%, <i>p </i>< 0.0006) compared with PEM alone (26.2 ± 6.5%). GC+PEM increased the CD4<sup>+</sup>LAG-3<sup>+</sup> T cells (4.9±1.2%, <i>p </i>< 0.03) compared with PEM alone (0.9 ± 0.3%), but did not affect CD4<sup>+</sup>PD-1<sup>+</sup> T cells. The effect of the drugs on synovial cells revealed that GC+PEM remarkably increased the CD14<sup>+</sup>LAG-3<sup>+</sup> cells in SFMCs (10.4 ± 2.0%, <i>p </i>< 0.0001) compared with PEM alone (0.6 ± 0.2%), but not the CD14<sup>+</sup>PD-1<sup>+</sup> cells. Thus, GC combined with ICI might exhibit contrasting activity via upregulation of CD4<sup>+</sup>LAG-3<sup>+</sup> T and CD14<sup>+</sup>LAG-3<sup>+</sup> cells in circulation and synovial milieu, respectively, possibly interfering with the ICI activity.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 8","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.70033","citationCount":"0","resultStr":"{\"title\":\"The Mitigating Effect of Combined Glucocorticoids with Immune Checkpoint Inhibitors on Lymphocyte Activation Gene-3 and Programmed Death-1 Expression\",\"authors\":\"Smadar Gertel, Ari Polachek, Victoria Furer, Tali Ofir Dovrat, Chen Avaky, Adi Broyde, Hila Nochimovitz, Ori Elkayam\",\"doi\":\"10.1002/eji.70033\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Cancer immunotherapy with immune checkpoint inhibitors (ICI) shows promising therapeutic efficacy but can cause immune-related adverse events (irAEs). Glucocorticoids (GCs) are commonly employed with ICI to mitigate irAEs. We had found previously that GCs upregulate significantly the inhibitory molecule, lymphocyte activation gene-3 (LAG-3) in peripheral blood and synovial fluid mononuclear cells (PBMCs and SFMCs, respectively). Here, we investigated the effect of GCs combined with ICI on LAG-3 and programmed death-1 (PD-1) expression in SFMCs of 32 inflammatory arthritis patients and PBMCs of 15 healthy controls. GC+Pembrolizumab (PEM, anti-PD-1) induced IL-10 and suppressed IFN-γ, TNF-α, and IL-17A mRNA expressions compared with PEM alone in PBMCs and SFMCs. PBMC proliferation was markedly inhibited by GC+PEM (3.5 ± 0.7%, <i>p </i>< 0.0006) compared with PEM alone (26.2 ± 6.5%). GC+PEM increased the CD4<sup>+</sup>LAG-3<sup>+</sup> T cells (4.9±1.2%, <i>p </i>< 0.03) compared with PEM alone (0.9 ± 0.3%), but did not affect CD4<sup>+</sup>PD-1<sup>+</sup> T cells. The effect of the drugs on synovial cells revealed that GC+PEM remarkably increased the CD14<sup>+</sup>LAG-3<sup>+</sup> cells in SFMCs (10.4 ± 2.0%, <i>p </i>< 0.0001) compared with PEM alone (0.6 ± 0.2%), but not the CD14<sup>+</sup>PD-1<sup>+</sup> cells. Thus, GC combined with ICI might exhibit contrasting activity via upregulation of CD4<sup>+</sup>LAG-3<sup>+</sup> T and CD14<sup>+</sup>LAG-3<sup>+</sup> cells in circulation and synovial milieu, respectively, possibly interfering with the ICI activity.</p>\",\"PeriodicalId\":165,\"journal\":{\"name\":\"European Journal of Immunology\",\"volume\":\"55 8\",\"pages\":\"\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2025-08-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.70033\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/eji.70033\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Immunology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/eji.70033","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
The Mitigating Effect of Combined Glucocorticoids with Immune Checkpoint Inhibitors on Lymphocyte Activation Gene-3 and Programmed Death-1 Expression
Cancer immunotherapy with immune checkpoint inhibitors (ICI) shows promising therapeutic efficacy but can cause immune-related adverse events (irAEs). Glucocorticoids (GCs) are commonly employed with ICI to mitigate irAEs. We had found previously that GCs upregulate significantly the inhibitory molecule, lymphocyte activation gene-3 (LAG-3) in peripheral blood and synovial fluid mononuclear cells (PBMCs and SFMCs, respectively). Here, we investigated the effect of GCs combined with ICI on LAG-3 and programmed death-1 (PD-1) expression in SFMCs of 32 inflammatory arthritis patients and PBMCs of 15 healthy controls. GC+Pembrolizumab (PEM, anti-PD-1) induced IL-10 and suppressed IFN-γ, TNF-α, and IL-17A mRNA expressions compared with PEM alone in PBMCs and SFMCs. PBMC proliferation was markedly inhibited by GC+PEM (3.5 ± 0.7%, p < 0.0006) compared with PEM alone (26.2 ± 6.5%). GC+PEM increased the CD4+LAG-3+ T cells (4.9±1.2%, p < 0.03) compared with PEM alone (0.9 ± 0.3%), but did not affect CD4+PD-1+ T cells. The effect of the drugs on synovial cells revealed that GC+PEM remarkably increased the CD14+LAG-3+ cells in SFMCs (10.4 ± 2.0%, p < 0.0001) compared with PEM alone (0.6 ± 0.2%), but not the CD14+PD-1+ cells. Thus, GC combined with ICI might exhibit contrasting activity via upregulation of CD4+LAG-3+ T and CD14+LAG-3+ cells in circulation and synovial milieu, respectively, possibly interfering with the ICI activity.
期刊介绍:
The European Journal of Immunology (EJI) is an official journal of EFIS. Established in 1971, EJI continues to serve the needs of the global immunology community covering basic, translational and clinical research, ranging from adaptive and innate immunity through to vaccines and immunotherapy, cancer, autoimmunity, allergy and more. Mechanistic insights and thought-provoking immunological findings are of interest, as are studies using the latest omics technologies. We offer fast track review for competitive situations, including recently scooped papers, format free submission, transparent and fair peer review and more as detailed in our policies.