Abstract
Background: With an increasing understanding of the antitumor immune response, considerable progress has been made in the field of tumor immunotherapy in the last decade. Inhibition of histone deacetylases represents a new strategy in tumor therapy and histone deacetylase inhibitors have been recently developed and validated as potential antitumor drugs. In addition to the direct antitumor effects, histone deacetylase inhibitors have been found to have the ability to improve tumor recognition by immune cells that may contribute to their antitumor activity. These immunomodolutory effects are desirable, and their in-depth comprehension will facilitate the design of novel regimens with improved clinical efficacy.
Objective: Our goal here is to review recent developments in the application of histone deacetylase inhibitors as immune modulators in cancer treatment.
Methods: Systemic compilation of the relevant literature in this field.
Results & Conclusion: In this review, we summarize recent advances in the understanding of how histone deacetylase inhibitors alter immune process and discuss their effects on various cytokines. We also discuss the challenges to optimize the use of these inhibitors as immune modulators in cancer treatment. Information gained from this review will be valuable to this field and may be helpful for designing tumor immunotherapy trials involving histone deacetylase inhibitors.
Keywords: Tumor immunotherapy, HDAC, HDAC inhibitors, antitumor, immune response, cytokine.
[http://dx.doi.org/10.1002/eji.201190035] [PMID: 21618503]
[http://dx.doi.org/10.1016/j.ccell.2015.10.012] [PMID: 26678337]
[http://dx.doi.org/10.1016/j.ejmech.2004.10.001] [PMID: 15642405]
[http://dx.doi.org/10.1002/med.20200] [PMID: 20162725]
[http://dx.doi.org/10.1016/S0959-437X(99)80006-9] [PMID: 10072350]
[PMID: 8622873]
[http://dx.doi.org/10.1038/35895] [PMID: 9486654]
[http://dx.doi.org/10.1038/35901] [PMID: 9486655]
[http://dx.doi.org/10.1126/science.1059262] [PMID: 1059262]
[http://dx.doi.org/10.1016/0092-8674(75)90107-5] [PMID: 1056809]
[http://dx.doi.org/10.1038/268462a0] [PMID: 268489]
[http://dx.doi.org/10.1016/0024-3205(80)90397-5] [PMID: 7003281]
[http://dx.doi.org/10.1038/35106079] [PMID: 11902574]
[http://dx.doi.org/10.1021/jm0303094] [PMID: 14613312]
[http://dx.doi.org/10.1021/jm7011408] [PMID: 18247554]
[http://dx.doi.org/10.1021/jm4001659] [PMID: 23627282]
[http://dx.doi.org/10.3390/molecules20033898] [PMID: 25738536]
[http://dx.doi.org/10.1016/j.leukres.2013.03.006] [PMID: 23582718]
[http://dx.doi.org/10.1016/j.bioorg.2016.05.005] [PMID: 27239721]
[http://dx.doi.org/10.1517/21678707.2016.1149467]
[http://dx.doi.org/10.2174/0929867323666151106125631] [PMID: 26549431]
[http://dx.doi.org/10.2217/epi.15.16] [PMID: 26111034]
[http://dx.doi.org/10.2217/epi.15.118] [PMID: 26950532]
[PMID: 21416059]
[http://dx.doi.org/10.1517/13543784.9.12.2923] [PMID: 11093362]
[http://dx.doi.org/10.1038/nrd4091] [PMID: 23989788]
[http://dx.doi.org/10.1002/ijc.22751] [PMID: 17455259]
[http://dx.doi.org/10.2174/09298673113209990191] [PMID: 23895688]
[http://dx.doi.org/10.1007/s11095-013-1089-1] [PMID: 23737346]
[http://dx.doi.org/10.1002/cncr.29175] [PMID: 25536954]
[http://dx.doi.org/10.1158/1535-7163.MCT-05-0442] [PMID: 16731764]
[http://dx.doi.org/10.1007/s00280-010-1344-7] [PMID: 20461381]
[http://dx.doi.org/10.1158/1078-0432.CCR-07-1126] [PMID: 18006784]
[http://dx.doi.org/10.1158/1078-0432.CCR-08-2365] [PMID: 19417023]
[http://dx.doi.org/10.7243/2049-7962-2-21] [PMID: 25520806]
[http://dx.doi.org/10.2217/fon.15.62] [PMID: 26043217]
[PMID: 12939461]
[http://dx.doi.org/10.1158/1078-0432.CCR-07-1786] [PMID: 18245542]
[http://dx.doi.org/10.1158/1078-0432.CCR-14-3119] [PMID: 25802282]
[http://dx.doi.org/10.1007/s40265-014-0275-8] [PMID: 25134672]
[http://dx.doi.org/10.1038/nature04870] [PMID: 16724054]
[http://dx.doi.org/10.1126/science.274.5288.782] [PMID: 8864118]
[http://dx.doi.org/10.1016/j.ccr.2010.05.023] [PMID: 20609351]
[http://dx.doi.org/10.1111/bph.12749] [PMID: 24780124]
[http://dx.doi.org/10.1002/mc.22024] [PMID: 23475695]
[http://dx.doi.org/10.1158/1078-0432.CCR-14-0968] [PMID: 25189481]
[http://dx.doi.org/10.1084/jem.20100643] [PMID: 20819927]
[http://dx.doi.org/10.2174/0929867033456675] [PMID: 14529481]
[http://dx.doi.org/10.1021/jm100007m] [PMID: 20205394]
[http://dx.doi.org/10.1021/jm200388e] [PMID: 21650221]
[http://dx.doi.org/10.1021/jm030235w] [PMID: 14521422]
[http://dx.doi.org/10.1042/BJ20070779] [PMID: 17868033]
[http://dx.doi.org/10.1038/sj.leu.2403522] [PMID: 15496978]
[PMID: 14578462]
[http://dx.doi.org/10.1089/10430340050015581] [PMID: 10757348]
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1456] [PMID: 19861533]
[http://dx.doi.org/10.1084/jem.184.1.19] [PMID: 8691133]
[http://dx.doi.org/10.4049/jimmunol.1001101] [PMID: 21368229]
[http://dx.doi.org/10.1021/jm980565u] [PMID: 10425110]
[http://dx.doi.org/10.1073/pnas.96.8.4592] [PMID: 10200307]
[PMID: 12414635]
[http://dx.doi.org/10.1038/sj.leu.2403388] [PMID: 15116122]
[http://dx.doi.org/10.1002/pros.20611] [PMID: 17520666]
[http://dx.doi.org/10.1158/2159-8290.CD-11-0214] [PMID: 22586682]
[PMID: 25667438]
[http://dx.doi.org/10.1111/bjh.13318] [PMID: 25712263]
[http://dx.doi.org/10.1038/nm1093] [PMID: 15322536]
[http://dx.doi.org/10.1371/journal.pone.0030815] [PMID: 22303460]
[http://dx.doi.org/10.1038/nm1652] [PMID: 17922010]
[http://dx.doi.org/10.1371/journal.pone.0007085] [PMID: 19759901]
[http://dx.doi.org/10.1182/blood.V97.10.3146] [PMID: 11342442]
[http://dx.doi.org/10.1007/s11095-013-1231-0] [PMID: 24203492]
[http://dx.doi.org/10.1111/imm.12136] [PMID: 23789844]
[http://dx.doi.org/10.1038/nm1039] [PMID: 15122249]
[http://dx.doi.org/10.1158/1078-0432.CCR-06-2903] [PMID: 17606727]
[http://dx.doi.org/10.2119/2006-00005.Dinarello] [PMID: 16557334]
[http://dx.doi.org/10.1002/hep.21054] [PMID: 16583461]
[http://dx.doi.org/10.1016/j.jhep.2004.10.020] [PMID: 15664246]
[PMID: 20560970]
[http://dx.doi.org/10.1111/bjh.12332] [PMID: 23573950]
[http://dx.doi.org/10.1182/blood-2006-03-014126] [PMID: 16684958]
[http://dx.doi.org/10.1016/j.nbd.2009.07.019] [PMID: 19635561]
[http://dx.doi.org/10.2119/molmed.2010.00152] [PMID: 21193899]
[http://dx.doi.org/10.1038/sj.leu.2404860] [PMID: 17637810]
[http://dx.doi.org/10.1016/S0140-6736(04)15736-X] [PMID: 15031034]
[http://dx.doi.org/10.1182/blood-2004-07-2909] [PMID: 15471951]
[PMID: 21115902]
[http://dx.doi.org/10.1074/jbc.M113.517599] [PMID: 24421314]
[http://dx.doi.org/10.1016/j.clim.2014.01.002] [PMID: 24503172]
[http://dx.doi.org/10.1021/jm800251w] [PMID: 18570366]
[http://dx.doi.org/10.1158/1535-7163.MCT-07-2026] [PMID: 18413790]
[http://dx.doi.org/10.1517/13543784.2011.577737] [PMID: 21554162]
[http://dx.doi.org/10.1358/dof.2007.032.04.1094476]
[http://dx.doi.org/10.2174/1568026615666150813145800] [PMID: 26268342]
[http://dx.doi.org/10.1016/j.canlet.2009.02.019] [PMID: 19344997]
[http://dx.doi.org/10.1007/s40265-015-0388-8] [PMID: 25837990]
[http://dx.doi.org/10.1371/journal.pone.0079502] [PMID: 24278143]
[http://dx.doi.org/10.1097/CMR.0b013e328364c0ed] [PMID: 23963286]
[http://dx.doi.org/10.1038/bcj.2014.58] [PMID: 25105535]
[http://dx.doi.org/10.1186/2051-1426-2-8] [PMID: 25054063]
[http://dx.doi.org/10.1038/leu.2010.244] [PMID: 21102427]
[http://dx.doi.org/10.1158/2326-6066.CIR-13-0188] [PMID: 24795358]
[http://dx.doi.org/10.1016/j.leukres.2014.09.004] [PMID: 25282334]
[http://dx.doi.org/10.1038/ncomms7838] [PMID: 25913720]
[http://dx.doi.org/10.7164/antibiotics.47.301] [PMID: 7513682]
[http://dx.doi.org/10.1038/ja.2011.35] [PMID: 21587264]
[http://dx.doi.org/10.2217/fon.13.220] [PMID: 24295412]
[PMID: 12208741]
[http://dx.doi.org/10.1038/sj.jid.5701216] [PMID: 18185535]
[http://dx.doi.org/10.1158/1078-0432.CCR-15-2584] [PMID: 26964571]
[http://dx.doi.org/10.7164/antibiotics.29.1] [PMID: 931784]
[http://dx.doi.org/10.1016/j.biocel.2008.05.026] [PMID: 18725319]
[PMID: 2211619]
[http://dx.doi.org/10.2174/0929867043365099] [PMID: 15180568]
[http://dx.doi.org/10.1016/j.drudis.2009.10.010] [PMID: 19897050]
[http://dx.doi.org/10.1038/onc.2015.46] [PMID: 25745993]
[http://dx.doi.org/10.1007/s00262-004-0513-0] [PMID: 14997346]
[http://dx.doi.org/10.1186/1479-5876-5-64] [PMID: 18070359]
[http://dx.doi.org/10.1007/s00262-007-0402-4] [PMID: 18046553]
[PMID: 17725605]
[http://dx.doi.org/10.1158/0008-5472.CAN-07-5270] [PMID: 19047136]
[http://dx.doi.org/10.1093/intimm/dxh326] [PMID: 16210330]
[PMID: 23564772]
[http://dx.doi.org/10.1189/jlb.0711339] [PMID: 22124136]
[http://dx.doi.org/10.1182/blood-2013-02-482513] [PMID: 23801635]
[http://dx.doi.org/10.1182/blood-2010-05-284711] [PMID: 20956800]
[PMID: 21416059]
[http://dx.doi.org/10.1182/blood-2007-06-098061] [PMID: 17962510]
[http://dx.doi.org/10.1007/s10637-008-9131-6] [PMID: 18425418]
[http://dx.doi.org/10.1200/JCO.2008.19.0694] [PMID: 19307505]
[http://dx.doi.org/10.1038/sj.onc.1210204] [PMID: 17322921]
[http://dx.doi.org/10.1182/blood-2008-01-133769] [PMID: 18541724]
[http://dx.doi.org/10.1016/j.cyto.2015.05.018] [PMID: 26255210]
[http://dx.doi.org/10.1182/blood.V99.2.618] [PMID: 11781246]
[http://dx.doi.org/10.1097/01.cji.0000211327.76266.65] [PMID: 17471161]
[http://dx.doi.org/10.1038/onc.2016.92] [PMID: 27086926]
[http://dx.doi.org/10.1200/JCO.2006.09.9861] [PMID: 17538176]
[http://dx.doi.org/10.1007/s00280-010-1302-4] [PMID: 20221600]
[http://dx.doi.org/10.1073/pnas.0437870100] [PMID: 12576549]
[http://dx.doi.org/10.1158/1078-0432.CCR-08-0122] [PMID: 18981013]
[http://dx.doi.org/10.1097/JTO.0b013e3181952478] [PMID: 19347984]
[http://dx.doi.org/10.1016/j.canlet.2014.10.034] [PMID: 25449774]
[http://dx.doi.org/10.1016/j.ccell.2016.08.001] [PMID: 27622335]
[http://dx.doi.org/10.1007/s11095-014-1300-z] [PMID: 24562809]
[http://dx.doi.org/10.1073/pnas.1011037108] [PMID: 21368108]
[http://dx.doi.org/10.1186/s12929-014-0111-1] [PMID: 25591912]
[http://dx.doi.org/10.4161/onci.27414] [PMID: 24701376]
[http://dx.doi.org/10.1038/bjc.2014.547] [PMID: 25393367]
[http://dx.doi.org/10.1038/srep21678] [PMID: 26902929]
[http://dx.doi.org/10.1158/0008-5472.CAN-13-0890] [PMID: 24158093]
[http://dx.doi.org/10.1016/j.canlet.2010.02.024] [PMID: 20346580]
[http://dx.doi.org/10.4068/cmj.2016.52.1.1] [PMID: 26865995]
[http://dx.doi.org/10.1038/icb.2011.95] [PMID: 22083528]
[http://dx.doi.org/10.1007/s10637-010-9596-y] [PMID: 21161327]
[http://dx.doi.org/10.1038/nrc1782] [PMID: 16397525]
[http://dx.doi.org/10.2217/imt.12.162] [PMID: 23413908]
[http://dx.doi.org/10.1038/nature10673] [PMID: 22193102]