Dexamethasone enhances programmed cell death 1 (PD-1) expression during T cell activation: an insight into the optimum application of glucocorticoids in anti-cancer therapy

BMC Immunology

Xianghua Wu²  Ping Zhang³  Bingxin Gu¹  Kailin Xing² 

[1]Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai 200032, China

[2]Department of Oncology, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai 200032, China

[3]Cancer Research Institute of Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai 200032, China

关键词: Memory T cells;    Naïve T cells;    Glucocorticoids;    PD-1;   

Others  :  1215978
DOI  :  10.1186/s12865-015-0103-2

 received in 2015-02-23, accepted in 2015-06-09,  发布年份 2015

【 摘 要 】

Background

Programmed cell death 1 (PD-1) is a key cell-surface receptor of CD28 superfamily that triggers inhibitory pathways to attenuate T-cell responses and promote T-cell tolerance. As a crucial role in tumor immunity, PD-1 has been a focus of studies in anti-cancer therapy. It has been approved that tumors could exploit PD-1-dependent immune suppression for immune evasion. Considering the wide use of glucocorticoids (GCs) in anti-cancer therapy and their immunosuppressive effects, we explored whether GCs could influence the expression of PD-1.

Results

In our study, we used dexamethasone (DEX) as a model glucocorticoid and demonstrated that DEX could enhance PD-1 expression in a dose-dependent manner. The effects were completely inhibited by the glucocorticoid receptor (GR) antagonist mifepristone (RU486), indicating that the effect of DEX on PD-1 is mediated through GR. We further found the sensitivity to DEX-induced upregulation of PD-1 expression had a significant difference between different T cell subsets, with memory T cells more susceptible to this effect. We also showed that DEX could suppress T cell functions via inhibition of cytokines production such as IL-2, IFN-γ, TNF-α and induction of apoptosis of T cells.

Conclusion

Our findings suggest a novel way by which DEX suppress the function of activated T lymphocytes by enhancing expression of PD-1 and provide an insight into the optimum clinical application of GCs.

【 授权许可】

   
2015 Xing et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

Fig. 6.

【 参考文献 】

• [1]Schmidt S, Rainer J, Ploner C, Presul E, Riml S, Kofler R. Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance. Cell Death Differ. 2004; 11 Suppl 1:S45-55.
• [2]Rutz HP, Herr I. Interference of glucocorticoids with apoptosis signaling and host-tumor interactions. Cancer Biol Ther. 2004; 3:715-8.
• [3]Rutz HP. Effects of corticosteroid use on treatment of solid tumours. Lancet. 2002; 360:1969-70.
• [4]Herr I, Pfitzenmaier J. Glucocorticoid use in prostate cancer and other solid tumours: implications for effectiveness of cytotoxic treatment and metastases. Lancet Oncol. 2006; 7:425-30.
• [5]Zhang C, Wenger T, Mattern J, Ilea S, Frey C, Gutwein P, Altevogt P, Bodenmuller W, Gassler N, Schnabel PA, et al. Clinical and mechanistic aspects of glucocorticoid-induced chemotherapy resistance in the majority of solid tumors. Cancer Biol Ther. 2007;6:278–87.
• [6]Zhang C, Beckermann B, Kallifatidis G, Liu Z, Rittgen W, Edler L, Buchler P, Debatin KM, Buchler MW, Friess H, et al. Corticosteroids induce chemotherapy resistance in the majority of tumour cells from bone, brain, breast, cervix, melanoma and neuroblastoma. Int J Oncol. 2006;29:1295–301.
• [7]Morita M, Suyama H, Igishi T, Shigeoka Y, Kodani M, Hashimoto K, Takeda K, Sumikawa T, Shimizu E. Dexamethasone inhibits paclitaxel-induced cytotoxic activity through retinoblastoma protein dephosphorylation in non-small cell lung cancer cells. Int J Oncol. 2007;30:187–92.
• [8]Brenes O, Arce F, Gatjens-Boniche O, Diaz C. Characterization of cell death events induced by anti-neoplastic drugs cisplatin, paclitaxel and 5-fluorouracil on human hepatoma cell lines: Possible mechanisms of cell resistance. Biomed Pharmacother. 2007; 61:347-55.
• [9]Xia M, Gasser J, Feige U. Dexamethasone enhances CTLA-4 expression during T cell activation. Cell Mol Life Sci. 1999; 55:1649-56.
• [10]Keir ME, Francisco LM, Sharpe AH. PD-1 and its ligands in T-cell immunity. Curr Opin Immunol. 2007; 19:309-14.
• [11]Chiou SH, Sheu BC, Chang WC, Huang SC, Hong-Nerng H. Current concepts of tumor-infiltrating lymphocytes in human malignancies. J Reprod Immunol. 2005; 67:35-50.
• [12]Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, Okazaki T, Tokura Y. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer Am Cancer Soc. 2010;116:1757–66.
• [13]Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, Krejci KG, Lobo JR, Sengupta S, Chen L, et al. Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A. 2004;101:17174–9.
• [14]Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother. 2007; 56:1173-82.
• [15]Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol. 1996;8:765–72.
• [16]Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, Shin T, Tsuchiya H, Pardoll DM, Okumura K, et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol. 2002;169:5538–45.
• [17]Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008; 26:677-704.
• [18]Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 2004; 173:945-54.
• [19]Franchimont D. Overview of the actions of glucocorticoids on the immune response: a good model to characterize new pathways of immunosuppression for new treatment strategies. Ann N Y Acad Sci. 2004; 1024:124-37.
• [20]Sprent J, Surh CD. Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells. Nat Immunol. 2011; 12:478-84.
• [21]Almawi WY, Beyhum HN, Rahme AA, Rieder MJ. Regulation of cytokine and cytokine receptor expression by glucocorticoids. J Leukoc Biol. 1996; 60:563-72.
• [22]Brown JA, Dorfman DM, Ma FR, Sullivan EL, Munoz O, Wood CR, Greenfield EA, Freeman GJ. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol. 2003;170:1257–66.
• [23]Paul S, Calmels B, Regulier E. Tumor-induced immunosuppression. Ann Biol Clin (Paris). 2002; 60:143-52.
• [24]Prestwich RJ, Errington F, Hatfield P, Merrick AE, Ilett EJ, Selby PJ, Melcher AA . The immune system–is it relevant to cancer development, progression and treatment? Clin Oncol (R Coll Radiol). 2008;20:101–12.
• [25]Shin DS, Ribas A. The evolution of checkpoint blockade as a cancer therapy: what's here, what's next? Curr Opin Immunol. 2015; 33C:23-35.
• [26]Ascierto PA. Immunotherapies and novel combinations: the focus of advances in the treatment of melanoma. Cancer Immunol Immunother. 2015; 64(3):271–4.