Increased PRAME-Specific CTL Killing of Acute Myeloid Leukemia Cells by Either a Novel Histone Deacetylase Inhibitor Chidamide Alone or Combined Treatment with Decitabine
As one of the best known cancer testis antigens, PRAME is overexpressed exclusively in germ line tissues such as the testis as well as in a variety of solid and hematological malignant cells including acute myeloid leukemia. Therefore, PRAME has been recognized as a promising target for both active and adoptive anti-leukemia immunotherapy. However, in most patients with PRAME-expressing acute myeloid leukemia, PRAME antigen-specific CD8+ CTL response are either undetectable or too weak to exert immune surveillance presumably due to the inadequate PRAME antigen expression and PRAME-specific antigen presentation by leukemia cells. In this study, we observed remarkably increased PRAME mRNA expression in human acute myeloid leukemia cell lines and primary acute myeloid leukemia cells after treatment with a novel subtype-selective histone deacetylase inhibitor chidamide in vitro. PRAME expression was further enhanced in acute myeloid leukemia cell lines after combined treatment with chidamide and DNA demethylating agent decitabine. Pre-treatment of an HLA-A0201+ acute myeloid leukemia cell line THP-1 with chidamide and/or decitabine increased sensitivity to purified CTLs that recognize PRAME100–108 or PRAME300–309 peptide presented by HLA-A0201. Chidamide-induced epigenetic upregulation of CD86 also contributed to increased cytotoxicity of PRAME antigen-specific CTLs. Our data thus provide a new line of evidence that epigenetic upregulation of cancer testis antigens by a subtype-selective HDAC inhibitor or in combination with hypomethylating agent increases CTL cytotoxicity and may represent a new opportunity in future design of treatment strategy targeting specifically PRAME-expressing acute myeloid leukemia.
References
[1]
Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ (2005) Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 5: 615–625.
[2]
Scanlan MJ, Gure AO, Jungbluth AA, Old LJ, Chen YT (2002) Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev 188: 22–32.
[3]
Atanackovic D, Luetkens T, Kloth B, Fuchs G, Cao Y, et al. (2011) Cancer-testis antigen expression and its epigenetic modulation in acute myeloid leukemia. Am J Hematol 86: 918–922.
[4]
Epping MT, Wang L, Edel MJ, Carlee L, Hernandez M, et al. (2005) The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling. Cell 122: 835–847.
[5]
Greiner J, Schmitt M, Li L, Giannopoulos K, Bosch K, et al. (2006) Expression of tumor-associated antigens in acute myeloid leukemia: Implications for specific immunotherapeutic approaches. Blood 108: 4109–4117.
[6]
Ortmann CA, Eisele L, Nuckel H, Klein-Hitpass L, Fuhrer A, et al. (2008) Aberrant hypomethylation of the cancer-testis antigen PRAME correlates with PRAME expression in acute myeloid leukemia. Ann Hematol 87: 809–818.
[7]
van Baren N, Chambost H, Ferrant A, Michaux L, Ikeda H, et al. (1998) PRAME, a gene encoding an antigen recognized on a human melanoma by cytolytic T cells, is expressed in acute leukaemia cells. Br J Haematol 102: 1376–1379.
[8]
Griffioen M, Kessler JH, Borghi M, van Soest RA, van der Minne CE, et al. (2006) Detection and functional analysis of CD8+ T cells specific for PRAME: a target for T-cell therapy. Clin Cancer Res 12: 3130–3136.
[9]
Kessler JH, Beekman NJ, Bres-Vloemans SA, Verdijk P, van Veelen PA, et al. (2001) Efficient identification of novel HLA-A(*)0201-presented cytotoxic T lymphocyte epitopes in the widely expressed tumor antigen PRAME by proteasome-mediated digestion analysis. J Exp Med 193: 73–88.
[10]
Yan M, Himoudi N, Basu BP, Wallace R, Poon E, et al. (2011) Increased PRAME antigen-specific killing of malignant cell lines by low avidity CTL clones, following treatment with 5-Aza-2′-Deoxycytidine. Cancer Immunol Immunother 60: 1243–1255.
[11]
Quintarelli C, Dotti G, De Angelis B, Hoyos V, Mims M, et al. (2008) Cytotoxic T lymphocytes directed to the preferentially expressed antigen of melanoma (PRAME) target chronic myeloid leukemia. Blood 112: 1876–1885.
[12]
Pollack SM, Li Y, Blaisdell MJ, Farrar EA, Chou J, et al. (2012) NYESO-1/LAGE-1s and PRAME are targets for antigen specific T cells in chondrosarcoma following treatment with 5-Aza-2-deoxycitabine. PLoS One 7: e32165.
[13]
Rezvani K, Yong AS, Tawab A, Jafarpour B, Eniafe R, et al. (2009) Ex vivo characterization of polyclonal memory CD8+ T-cell responses to PRAME-specific peptides in patients with acute lymphoblastic leukemia and acute and chronic myeloid leukemia. Blood 113: 2245–2255.
[14]
Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, et al. (2005) Clinical development of histone deacetylase inhibitors as anticancer agents. Annu Rev Pharmacol Toxicol 45: 495–528.
[15]
Szyf M (2009) Epigenetics, DNA methylation, and chromatin modifying drugs. Annu Rev Pharmacol Toxicol 49: 243–263.
[16]
Cruz CR, Gerdemann U, Leen AM, Shafer JA, Ku S, et al. (2011) Improving T-cell therapy for relapsed EBV-negative Hodgkin lymphoma by targeting upregulated MAGE-A4. Clin Cancer Res 17: 7058–7066.
[17]
Dubovsky JA, McNeel DG, Powers JJ, Gordon J, Sotomayor EM, et al. (2009) Treatment of chronic lymphocytic leukemia with a hypomethylating agent induces expression of NXF2, an immunogenic cancer testis antigen. Clin Cancer Res 15: 3406–3415.
[18]
Gong K, Xie J, Yi H, Li W (2012) CS055 (Chidamide/HBI-8000), a novel histone deacetylase inhibitor, induces G1 arrest, ROS-dependent apoptosis and differentiation in human leukaemia cells. Biochem J 443: 735–746.
[19]
Liu L, Chen B, Qin S, Li S, He X, et al. (2010) A novel histone deacetylase inhibitor Chidamide induces apoptosis of human colon cancer cells. Biochem Biophys Res Commun 392: 190–195.
[20]
Natsume A, Wakabayashi T, Tsujimura K, Shimato S, Ito M, et al. (2008) The DNA demethylating agent 5-aza-2′-deoxycytidine activates NY-ESO-1 antigenicity in orthotopic human glioma. Int J Cancer 122: 2542–2553.
[21]
Skov S, Pedersen MT, Andresen L, Straten PT, Woetmann A, et al. (2005) Cancer cells become susceptible to natural killer cell killing after exposure to histone deacetylase inhibitors due to glycogen synthase kinase-3-dependent expression of MHC class I-related chain A and B. Cancer Res. 65: 11136–11145.
[22]
Vo DD, Prins RM, Begley JL, Donahue TR, Morris LF, et al. (2009) Enhanced antitumor activity induced by adoptive T-cell transfer and adjunctive use of the histone deacetylase inhibitor LAQ824. Cancer Res 69: 8693–8699.
[23]
Weber J, Salgaller M, Samid D, Johnson B, Herlyn M, et al. (1994) Expression of the MAGE-1 tumor antigen is up-regulated by the demethylating agent 5-aza-2′-deoxycytidine. Cancer Res 54: 1766–1771.
[24]
Weiser TS, Guo ZS, Ohnmacht GA, Parkhurst ML, Tong-On P, et al. (2001) Sequential 5-Aza-2 deoxycytidine-depsipeptide FR901228 treatment induces apoptosis preferentially in cancer cells and facilitates their recognition by cytolytic T lymphocytes specific for NY-ESO-1. J Immunother 24: 151–161.
[25]
Goodyear O, Agathanggelou A, Novitzky-Basso I, Siddique S, McSkeane T, et al. (2010) Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood 116: 1908–1918.
[26]
Akers SN, Odunsi K, Karpf AR (2010) Regulation of cancer germline antigen gene expression: implications for cancer immunotherapy. Future Oncol 6: 717–732.
[27]
Rossi LE, Avila DE, Spallanzani RG, Ziblat A, Fuertes MB, et al. (2012) Histone deacetylase inhibitors impair NK cell viability and effector functions through inhibition of activation and receptor expression. J Leukoc Biol 91: 321–331.
[28]
Rosborough BR, Castellaneta A, Natarajan S, Thomson AW, Turnquist HR (2012) Histone deacetylase inhibition facilitates GM-CSF-mediated expansion of myeloid-derived suppressor cells in vitro and in vivo. J Leukoc Biol 91: 701–709.
[29]
Song W, Tai YT, Tian Z, Hideshima T, Chauhan D, et al. (2011) HDAC inhibition by LBH589 affects the phenotype and function of human myeloid dendritic cells. Leukemia 25: 161–168.
[30]
Shen L, Ciesielski M, Ramakrishnan S, Miles KM, Ellis L, et al. (2012) Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models. PLoS One 7: e30815.
[31]
Ning ZQ, Li ZB, Newman MJ, Shan S, Wang XH, et al. (2012) Chidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity. Cancer Chemother Pharmacol 69: 901–909.
[32]
Maeda T, Towatari M, Kosugi H, Saito H (2000) Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells. Blood 96: 3847–3856.
[33]
Riddell SR, Greenberg PD (1990) The use of anti-CD3 and anti-CD28 monoclonal antibodies to clone and expand human antigen-specific T cells. J Immunol Methods 128: 189–201.
[34]
Xia S, Guo Z, Yao Y, Xu X, Yi H, et al. (2008) Liver stroma enhances activation of TLR3-triggered NK cells through fibronectin. Mol Immunol 45: 2831–2838.
[35]
Epping MT, Wang L, Plumb JA, Lieb M, Gronemeyer H, et al. (2007) A functional genetic screen identifies retinoic acid signaling as a target of histone deacetylase inhibitors. Proc Natl Acad Sci U S A 104: 17777–17782.
[36]
Santamaria C, Chillon MC, Garcia-Sanz R, Balanzategui A, Sarasquete ME, et al. (2008) The relevance of preferentially expressed antigen of melanoma (PRAME) as a marker of disease activity and prognosis in acute promyelocytic leukemia. Haematologica 93: 1797–1805.
[37]
Steinbach D, Hermann J, Viehmann S, Zintl F, Gruhn B (2002) Clinical implications of PRAME gene expression in childhood acute myeloid leukemia. Cancer Genet Cytogenet 133: 118–123.
[38]
Tajeddine N, Louis M, Vermylen C, Gala JL, Tombal B, et al. (2008) Tumor associated antigen PRAME is a marker of favorable prognosis in childhood acute myeloid leukemia patients and modifies the expression of S100A4, Hsp 27, p21, IL-8 and IGFBP-2 in vitro and in vivo. Leuk Lymphoma 49: 1123–1131.
[39]
Doolan P, Clynes M, Kennedy S, Mehta JP, Crown J, et al. (2008) Prevalence and prognostic and predictive relevance of PRAME in breast cancer. Breast Cancer Res Treat 109: 359–365.
[40]
Oberthuer A, Hero B, Spitz R, Berthold F, Fischer M (2004) The tumor-associated antigen PRAME is universally expressed in high-stage neuroblastoma and associated with poor outcome. Clin Cancer Res 10: 4307–4313.
[41]
Carreno BM, Collins M (2002) The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annu Rev Immunol 20: 29–53.
Fooksman DR, Vardhana S, Vasiliver-Shamis G, Liese J, Blair DA, et al. (2010) Functional anatomy of T cell activation and synapse formation. Annu Rev Immunol 28: 79–105.
[44]
Qin T, Youssef EM, Jelinek J, Chen R, Yang AS, et al. (2007) Effect of cytarabine and decitabine in combination in human leukemic cell lines. Clin Cancer Res 13: 4225–4232.
[45]
Agarwal P, Raghavan A, Nandiwada SL, Curtsinger JM, Bohjanen PR, et al. (2009) Gene regulation and chromatin remodeling by IL-12 and type I IFN in programming for CD8 T cell effector function and memory. J Immunol 183: 1695–1704.
[46]
Choi J, Ritchey J, Prior JL, Holt M, Shannon WD, et al. (2010) In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood 116: 129–139.
[47]
Fann M, Godlove JM, Catalfamo M, Wood WH, 3rd, Chrest FJ, et al (2006) Histone acetylation is associated with differential gene expression in the rapid and robust memory CD8(+) T-cell response. Blood 108: 3363–3370.
[48]
Reddy P, Sun Y, Toubai T, Duran-Struuck R, Clouthier SG, et al. (2008) Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice. J Clin Invest 118: 2562–2573.
[49]
Northrop JK, Wells AD, Shen H (2008) Cutting edge: chromatin remodeling as a molecular basis for the enhanced functionality of memory CD8 T cells. J Immunol 181: 865–868.
[50]
Carta S, Tassi S, Semino C, Fossati G, Mascagni P, et al. (2006) Histone deacetylase inhibitors prevent exocytosis of interleukin-1beta-containing secretory lysosomes: role of microtubules. Blood 108: 1618–1626.
