摘要
最近成功的检查点阻断抗体引发了癌症免疫治疗的革命。检查点抑制激活适应性免疫系统,导致对一系列肿瘤类型产生持久的应答,尽管这种应答仅限于存在肿瘤浸润T细胞的患者群体。刺激免疫系统引发抗肿瘤反应的策略备受关注,目前有几个研究小组正致力于开发激活模式识别受体(PRRs)的药物,PRRs是一种能够检测致病性和损伤相关分子并通过激活先天免疫反应来做出反应的蛋白质。尽管早期的研究主要集中在膜结合PRRs的Toll样受体(TLR)家族上,但TLR的激活已被证实与促肿瘤和抗肿瘤作用相关。尽管如此,在一系列临床试验中,TLR激动剂已被作为潜在的抗癌药物使用。最近,随着早期临床数据的出现,IFN基因(STING)的细胞质PRR刺激因子(cytosolic PRR刺激物)作为另一个有前景的抗癌药物开发靶点引起了人们的关注。除了STING,其他几个细胞内PRR靶点也引起了药物研发界的兴趣,包括RIG-Ilike受体(RLRs)和nod样受体(NLRs)。在这篇综述中,我们描述了PRRs激活剂作为抗癌治疗药物的前景,并对比了早期TLR激动剂与细胞内PRR激活剂的研究进展,包括作为单一药物和与其他癌症免疫疗法联合使用。
关键词: 免疫肿瘤学,先天免疫,模式识别受体,癌症免疫治疗,TLRs
[http://dx.doi.org/10.1016/j.immuni.2013.07.012 ] [PMID: 23890059]
[http://dx.doi.org/10.3389/fimmu.2014.00459 ] [PMID: 25295041]
[http://dx.doi.org/10.1097/00000658-189112000-00015 ] [PMID: 17859590]
[http://dx.doi.org/10.1016/j.ccr.2010.06.010 ] [PMID: 20609349]
[http://dx.doi.org/10.1016/S0140-6736(98)07422-4 ] [PMID: 10335805]
[http://dx.doi.org/10.1136/bmj.1.5023.841 ] [PMID: 13413231]
[http://dx.doi.org/10.1038/ni1102-991 ] [PMID: 12407406]
[http://dx.doi.org/10.1038/nrc.2017.117 ] [PMID: 29326431]
[http://dx.doi.org/10.1056/NEJMoa1003466 ] [PMID: 20525992]
[http://dx.doi.org/10.1056/NEJMoa1104621 ] [PMID: 21639810]
[http://dx.doi.org/10.1200/JCO.2014.56.2736 ] [PMID: 25667295]
[http://dx.doi.org/10.1016/j.ejca.2015.08.012 ] [PMID: 26364516]
[http://dx.doi.org/10.1128/MCB.25.21.9543-9553.2005 ] [PMID: 16227604]
[http://dx.doi.org/10.1038/nrd4591 ] [PMID: 26228759]
[http://dx.doi.org/10.1038/nrc.2016.36 ] [PMID: 27079802]
[http://dx.doi.org/10.1615/CritRevImmunol.v28.i2.10 ] [PMID: 18540826]
[http://dx.doi.org/10.3109/08830185.2010.529976 ] [PMID: 21235323]
[http://dx.doi.org/10.1038/nri3479 ] [PMID: 23846113]
[http://dx.doi.org/10.1016/j.ejmech.2017.12.026 ] [PMID: 29268133]
[http://dx.doi.org/10.1016/j.cell.2010.01.022 ] [PMID: 20303872]
[http://dx.doi.org/10.1038/nri2569 ] [PMID: 19521399]
[http://dx.doi.org/10.1038/nri3446 ] [PMID: 23681101]
[http://dx.doi.org/10.1038/nri1391 ] [PMID: 15229469]
[http://dx.doi.org/10.1189/jlb.5MR0217-059RR ] [PMID: 28729358]
[http://dx.doi.org/10.2174/0929867324666170320114359 ] [PMID: 28322156]
[http://dx.doi.org/10.2174/138161206778743493 ] [PMID: 17100620]
[http://dx.doi.org/10.2174/092986706776872916 ] [PMID: 16719784]
[http://dx.doi.org/10.1111/j.1582-4934.2010.01127.x ] [PMID: 20629986]
[http://dx.doi.org/10.1016/j.molcel.2014.03.040 ] [PMID: 24766893]
[http://dx.doi.org/10.1016/j.cytogfr.2014.05.004 ] [PMID: 24894317]
[http://dx.doi.org/10.1111/j.1600-065X.2011.01052.x ] [PMID: 21884169]
[http://dx.doi.org/10.1016/j.cytogfr.2014.07.001 ] [PMID: 25070125]
[http://dx.doi.org/10.1038/nature07317 ] [PMID: 18724357]
[http://dx.doi.org/10.1038/nature08476 ] [PMID: 19776740]
[http://dx.doi.org/10.1158/1078-0432.CCR-15-1362 ] [PMID: 26373573]
[http://dx.doi.org/10.1038/nrd.2017.264 ] [PMID: 29282375]
[http://dx.doi.org/10.1111/j.1600-065X.2011.01043.x ] [PMID: 21884174]
[http://dx.doi.org/10.1111/imr.12286 ] [PMID: 25879282]
[http://dx.doi.org/10.1016/j.cell.2010.01.040 ] [PMID: 20303873]
[http://dx.doi.org/10.1038/cmi.2015.95 ] [PMID: 26549800]
[http://dx.doi.org/10.1016/j.tcb.2013.12.002 ] [PMID: 24439965]
[http://dx.doi.org/10.7554/eLife.00291 ] [PMID: 23426999]
[http://dx.doi.org/10.1016/j.imbio.2008.11.012 ] [PMID: 19250701]
[http://dx.doi.org/10.4049/jimmunol.1502599 ] [PMID: 27022193]
[http://dx.doi.org/10.1038/nature07830 ] [PMID: 19252480]
[http://dx.doi.org/10.1016/j.cell.2007.09.008 ] [PMID: 17889651]
[http://dx.doi.org/10.1016/j.immuni.2016.09.011 ] [PMID: 27742543]
[http://dx.doi.org/10.1126/science.1229159 ] [PMID: 23520111]
[http://dx.doi.org/10.1038/nature14138 ] [PMID: 25686612]
[http://dx.doi.org/10.1126/science.285.5425.248 ] [PMID: 10398600]
[http://dx.doi.org/10.1038/onc.2013.302 ] [PMID: 23934186]
[http://dx.doi.org/10.1016/j.ccr.2009.01.001 ] [PMID: 19185845]
[PMID: 18219394]
[http://dx.doi.org/10.1016/j.ccr.2008.10.011 ] [PMID: 18977329]
[http://dx.doi.org/10.1158/0008-5472.CAN-13-2698 ] [PMID: 25074614]
[http://dx.doi.org/10.1021/jm049211v ] [PMID: 15887957]
[http://dx.doi.org/10.1097/00001432-200304000-00004 ] [PMID: 12734440]
[PMID: 1377595]
[http://dx.doi.org/10.4103/0253-7613.161249 ] [PMID: 26288465]
[http://dx.doi.org/10.1038/bjc.1996.569 ] [PMID: 8912549]
[http://dx.doi.org/10.1016/j.jhep.2007.02.025 ] [PMID: 17532523]
[http://dx.doi.org/10.1080/2162402X.2015.1088631 ] [PMID: 27141345]
[http://dx.doi.org/10.1200/JCO.2006.07.9129 ] [PMID: 17179105]
[http://dx.doi.org/10.1200/JCO.2010.32.8971 ] [PMID: 21632509]
[http://dx.doi.org/10.1038/nrd3775 ] [PMID: 22743965]
[http://dx.doi.org/10.1016/j.critrevonc.2014.12.002 ] [PMID: 25577571]
[http://dx.doi.org/10.1158/1078-0432.CCR-16-1934 ] [PMID: 27810904]
[http://dx.doi.org/10.1371/journal.pone.0148764 ] [PMID: 26928328]
[http://dx.doi.org/10.4049/jimmunol.1101304 ] [PMID: 22231700]
[http://dx.doi.org/10.3389/fonc.2016.00233 ] [PMID: 27847783]
[http://dx.doi.org/10.1172/jci.insight.93397 ] [PMID: 28931759]
[http://dx.doi.org/10.1016/j.cell.2009.07.021 ] [PMID: 19665965]
[http://dx.doi.org/10.1126/science.1229963 ] [PMID: 23258412]
[http://dx.doi.org/10.1126/science.1232458 ] [PMID: 23258413]
[http://dx.doi.org/10.1038/ng1845 ] [PMID: 16845398]
[http://dx.doi.org/10.1038/ng2091 ] [PMID: 17660818]
[http://dx.doi.org/10.1016/j.celrep.2015.09.007 ] [PMID: 26440888]
[http://dx.doi.org/10.1038/ni.3356 ] [PMID: 26829768]
[http://dx.doi.org/10.1016/j.immuni.2013.10.019 ] [PMID: 24332030]
[http://dx.doi.org/10.1016/j.celrep.2014.01.003 ] [PMID: 24462292]
[http://dx.doi.org/10.1038/ni.3558 ] [PMID: 27648547]
[http://dx.doi.org/10.1038/nsmb.2331 ] [PMID: 22728658]
[http://dx.doi.org/10.1038/nature12640 ] [PMID: 24077100]
[http://dx.doi.org/10.1038/nature18268 ] [PMID: 27225120]
[http://dx.doi.org/10.1126/scisignal.2002521 ] [PMID: 22394562]
[http://dx.doi.org/10.1128/JVI.00037-14 ] [PMID: 24600004]
[http://dx.doi.org/10.4049/jimmunol.1700699 ]
[PMID: 14555498]
[http://dx.doi.org/10.4049/jimmunol.1401869 ] [PMID: 25385820]
[http://dx.doi.org/10.1016/j.immuni.2014.10.017 ] [PMID: 25517615]
[http://dx.doi.org/10.1074/jbc.M112.382986 ] [PMID: 23027866]
[http://dx.doi.org/10.4049/jimmunol.1300097 ] [PMID: 23585680]
[http://dx.doi.org/10.1021/cb400264n ] [PMID: 23683494]
[http://dx.doi.org/10.4049/jimmunol.178.4.2171 ] [PMID: 17277122]
[http://dx.doi.org/10.1158/2326-6066.CIR-13-0123 ] [PMID: 24913717]
[http://dx.doi.org/10.1016/j.bmcl.2008.08.088 ] [PMID: 18799311]
[http://dx.doi.org/10.1371/journal.pone.0077846 ] [PMID: 24204993]
[http://dx.doi.org/10.1038/nchembio.1661 ] [PMID: 25344812]
[http://dx.doi.org/10.1016/j.celrep.2015.04.031 ] [PMID: 25959818]
[http://dx.doi.org/10.1021/acs.jmedchem.6b01300 ] [PMID: 27783523]
[http://dx.doi.org/10.1038/s41586-018-0705-y ] [PMID: 30405246]
[http://dx.doi.org/10.1016/j.antiviral.2017.10.001 ] [PMID: 28982551]
[http://dx.doi.org/10.1038/nature04734 ] [PMID: 16625202]
[http://dx.doi.org/10.1038/nature13590 ] [PMID: 25119032]
[http://dx.doi.org/10.1126/sciadv.1701854 ] [PMID: 29492454]
[http://dx.doi.org/10.1074/jbc.M807547200 ] [PMID: 19122199]
[http://dx.doi.org/10.1073/pnas.1515152113 ] [PMID: 26733676]
[http://dx.doi.org/10.1016/j.cell.2011.09.039 ] [PMID: 22000019]
[http://dx.doi.org/10.1038/nature10537 ] [PMID: 21947008]
[http://dx.doi.org/10.1016/j.cell.2012.11.048 ] [PMID: 23273991]
[http://dx.doi.org/10.1074/jbc.M900818200 ] [PMID: 19278996]
[http://dx.doi.org/10.1016/j.cyto.2015.02.010 ] [PMID: 25794939]
[PMID: 29351913]
[http://dx.doi.org/10.18632/oncotarget.25626 ] [PMID: 29989043]
[http://dx.doi.org/10.1038/nm.1887 ] [PMID: 18978796]
[http://dx.doi.org/10.1038/cdd.2014.96 ] [PMID: 25012502]
[http://dx.doi.org/10.1172/JCI37155 ] [PMID: 19620789]
[http://dx.doi.org/10.1002/stem.1350 ] [PMID: 23390110]
[PMID: 21728171]
[http://dx.doi.org/10.1158/0008-5472.CAN-18-0730 ] [PMID: 30224377]
[http://dx.doi.org/10.1016/j.coi.2008.06.001 ] [PMID: 18585455]
[http://dx.doi.org/10.1073/pnas.1306376110 ] [PMID: 23940371]
[http://dx.doi.org/10.1016/j.immuni.2011.12.018 ] [PMID: 22386589]
[http://dx.doi.org/10.1016/j.immuni.2008.02.005 ] [PMID: 18341998]
[http://dx.doi.org/10.1016/j.molcel.2014.02.018 ] [PMID: 24657167]
[http://dx.doi.org/10.1186/s13104-018-3335-4 ] [PMID: 29615116]
[http://dx.doi.org/10.4049/jimmunol.178.4.2380 ] [PMID: 17277144]
[http://dx.doi.org/10.1016/j.jmb.2006.09.067 ] [PMID: 17054981]
[http://dx.doi.org/10.1016/j.bbrc.2006.11.122 ] [PMID: 17173864]
[http://dx.doi.org/10.1074/jbc.M111.278812 ] [PMID: 21880711]
[http://dx.doi.org/10.1074/jbc.M112.407130 ] [PMID: 22948162]
[http://dx.doi.org/10.1016/j.tibs.2016.09.002 ] [PMID: 27669650]
[http://dx.doi.org/10.3389/fphar.2015.00262 ] [PMID: 26594174]
[http://dx.doi.org/10.1038/ni.2224 ] [PMID: 22430787]
[http://dx.doi.org/10.3389/fimmu.2014.00185 ] [PMID: 24795727]
[http://dx.doi.org/10.1158/2326-6066.CIR-16-0269 ] [PMID: 28093447]
[http://dx.doi.org/10.1016/j.immuni.2015.08.013 ] [PMID: 26384545]
[http://dx.doi.org/10.1084/jem.20161707 ] [PMID: 28442553]
[http://dx.doi.org/10.1038/nature04515 ] [PMID: 16407890]
[http://dx.doi.org/10.1021/acsmedchemlett.8b00416 ] [PMID: 30344900]