Abstract
Objective: Recent scientific advances have expanded insight into the immune system and its response to malignant cells. In the past few years, immunotherapy has attained a hallmark for cancer treatment, especially for patients suffering from the advanced-stage disease. Modulating the immune system by blocking various immune checkpoint receptor proteins through monoclonal antibodies has improved cancer patients' survival rates.
Methods: The scope of this review spans from 1985 to the present day. Many journals, books, and theses have been used to gather data, as well as Internet-based information such as Wiley, PubMed, Google Scholar, ScienceDirect, EBSCO, SpringerLink, and Online electronic journals.
Key Findings: Current review elaborates on the potential inhibitory and stimulatory checkpoint pathways which are emerged and have been tested in various preclinical models, clinical trials, and practices. Twenty-odd such significant checkpoints are identified and discussed in the present work.
Conclusion: A large number of ongoing studies reveal that combination therapies that target more than one signaling pathway may become effective in order to maximize efficacy and minimize toxicity. Moreover, these immunotherapy targets can be a part of integrated therapeutic strategies in addition to classical approaches. It may become a paradigm shift as a promising strategy for cancer treatment.
Graphical Abstract
[http://dx.doi.org/10.1517/14728222.2013.733001] [PMID: 23173842]
[http://dx.doi.org/10.1634/stemcells.2004-0107] [PMID: 15749935]
[PMID: 23304670]
[http://dx.doi.org/10.18632/oncotarget.24724] [PMID: 29707117]
[http://dx.doi.org/10.2147/BCTT.S176070] [PMID: 31040712]
[http://dx.doi.org/10.1177/1559827617700600] [PMID: 30202392]
[http://dx.doi.org/10.1053/srao.2000.6590] [PMID: 11034629]
[http://dx.doi.org/10.3390/cancers3033279] [PMID: 24212956]
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[http://dx.doi.org/10.1093/pcmedi/pby011] [PMID: 30687562]
[http://dx.doi.org/10.1053/j.seminoncol.2014.09.004] [PMID: 25438997]
[http://dx.doi.org/10.1097/CM9.0000000000001490] [PMID: 34039862]
[http://dx.doi.org/10.5114/ceji.2018.77390] [PMID: 30135633]
[http://dx.doi.org/10.20892/j.issn.2095-3941.2018.0493] [PMID: 31565479]
[http://dx.doi.org/10.4103/jcrt.JCRT_1241_20] [PMID: 34528529]
[http://dx.doi.org/10.20892/j.issn.2095-3941.2017.0086] [PMID: 29951336]
[http://dx.doi.org/10.1136/jclinpath-2017-204853] [PMID: 29097600]
[http://dx.doi.org/10.1016/j.ctrv.2015.11.001] [PMID: 26589760]
[http://dx.doi.org/10.1080/21645515.2019.1571892] [PMID: 30888929]
[http://dx.doi.org/10.2174/1389203719666180928105632] [PMID: 30264678]
[http://dx.doi.org/10.1126/scitranslmed.aad7118] [PMID: 26936508]
[http://dx.doi.org/10.3389/fphar.2017.00561] [PMID: 28878676]
[http://dx.doi.org/10.1186/s13045-019-0779-5] [PMID: 31488176]
[http://dx.doi.org/10.18632/oncotarget.23279] [PMID: 29423118]
[http://dx.doi.org/10.1186/s40425-018-0316-z] [PMID: 29357948]
[http://dx.doi.org/10.1016/j.imlet.2007.10.010] [PMID: 18035425]
[http://dx.doi.org/10.1038/328267a0] [PMID: 3496540]
[http://dx.doi.org/10.1046/j.1440-1711.1999.00795.x] [PMID: 10101680]
[http://dx.doi.org/10.1002/1521-4141(200204)32:4<972::AID-IMMU972>3.0.CO;2-M] [PMID: 11920563]
[http://dx.doi.org/10.1182/blood-2011-11-388918] [PMID: 22403258]
[http://dx.doi.org/10.1046/j.1365-2567.2000.00121.x] [PMID: 11012769]
[http://dx.doi.org/10.1182/blood-2017-06-741033] [PMID: 29118008]
[http://dx.doi.org/10.1111/imr.12530] [PMID: 28258701]
[http://dx.doi.org/10.1155/2014/215763]
[http://dx.doi.org/10.4049/jimmunol.177.2.1052] [PMID: 16818761]
[http://dx.doi.org/10.1084/jem.188.10.1849] [PMID: 9815262]
[http://dx.doi.org/10.1634/theoncologist.13-S4-2] [PMID: 19001145]
[http://dx.doi.org/10.1046/j.1365-2567.1999.00888.x] [PMID: 10583602]
[http://dx.doi.org/10.1016/j.it.2018.10.009] [PMID: 30497614]
[http://dx.doi.org/10.1172/JCI84236] [PMID: 26345422]
[http://dx.doi.org/10.4049/jimmunol.1402176] [PMID: 25780040]
[http://dx.doi.org/10.18632/genesandcancer.180] [PMID: 30603054]
[http://dx.doi.org/10.3892/ol.2020.12070] [PMID: 32963613]
[http://dx.doi.org/10.1016/j.redox.2019.101174] [PMID: 30917934]
[http://dx.doi.org/10.1016/j.immuni.2016.05.001] [PMID: 27192565]
[http://dx.doi.org/10.1038/s41590-018-0217-9] [PMID: 30349037]
[http://dx.doi.org/10.4049/jimmunol.1002050] [PMID: 21441454]
[http://dx.doi.org/10.18632/oncotarget.4751] [PMID: 26318293]
[http://dx.doi.org/10.4049/jimmunol.172.9.5450] [PMID: 15100286]
[http://dx.doi.org/10.1080/2162402X.2020.1756116] [PMID: 32923111]
[http://dx.doi.org/10.1186/1479-5876-12-97] [PMID: 24726012]
[http://dx.doi.org/10.1136/esmoopen-2019-000544] [PMID: 32516116]
[http://dx.doi.org/10.1172/JCI31184] [PMID: 17932562]
[http://dx.doi.org/10.1158/0008-5472.CAN-13-2690] [PMID: 24769443]
[http://dx.doi.org/10.4049/jimmunol.1102609] [PMID: 22422881]
[http://dx.doi.org/10.1111/imr.12520] [PMID: 28258697]
[http://dx.doi.org/10.3389/fimmu.2013.00449] [PMID: 24339828]
[http://dx.doi.org/10.1016/j.molmed.2005.06.008] [PMID: 16002337]
[PMID: 27471694]
[http://dx.doi.org/10.1111/j.1600-065X.2009.00772.x] [PMID: 19426227]
[http://dx.doi.org/10.1111/j.0105-2896.2010.00903.x] [PMID: 20536563]
[http://dx.doi.org/10.3390/ijms18030645] [PMID: 28300768]
[http://dx.doi.org/10.1038/ni1271] [PMID: 16286920]
[http://dx.doi.org/10.1182/blood-2011-11-389585] [PMID: 22438246]
[http://dx.doi.org/10.1038/cddis.2015.162] [PMID: 26086965]
[http://dx.doi.org/10.3748/wjg.v22.i7.2294] [PMID: 26900291]
[http://dx.doi.org/10.2147/OTT.S170385] [PMID: 30410357]
[PMID: 26339368]
[http://dx.doi.org/10.1136/jitc-2020-000911] [PMID: 32601081]
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0039] [PMID: 24795351]
[http://dx.doi.org/10.1038/ni.1674] [PMID: 19011627]
[http://dx.doi.org/10.1002/eji.201041136] [PMID: 21416464]
[http://dx.doi.org/10.1111/cei.13407] [PMID: 31828774]
[http://dx.doi.org/10.1172/JCI81187] [PMID: 26413872]
[http://dx.doi.org/10.1016/j.it.2016.10.002] [PMID: 27793572]
[http://dx.doi.org/10.3390/cancers11060877] [PMID: 31234588]
[http://dx.doi.org/10.3390/ijms21030922] [PMID: 32019260]
[http://dx.doi.org/10.1093/intimm/dxh059] [PMID: 15039383]
[http://dx.doi.org/10.1073/pnas.1120606109] [PMID: 22421438]
[http://dx.doi.org/10.1136/jitc-2020-000957] [PMID: 32900861]
[http://dx.doi.org/10.3892/ol.2021.12916] [PMID: 34386077]
[http://dx.doi.org/10.1111/cas.13324] [PMID: 28730595]
[http://dx.doi.org/10.1073/pnas.0903474106] [PMID: 19815499]
[http://dx.doi.org/10.1038/cdd.2012.141] [PMID: 23154388]
[http://dx.doi.org/10.4049/jimmunol.1700407] [PMID: 29500245]
[http://dx.doi.org/10.1182/blood-2018-01-825265] [PMID: 29986909]
[http://dx.doi.org/10.1111/imr.12518] [PMID: 28258695]
[http://dx.doi.org/10.1038/s41379-019-0364-z] [PMID: 31537897]
[http://dx.doi.org/10.1158/0008-5472.CAN-13-1504] [PMID: 24691993]
[http://dx.doi.org/10.1084/jem.20100619] [PMID: 21383057]
[http://dx.doi.org/10.1136/jitc-2020-000695] [PMID: 32273348]
[http://dx.doi.org/10.1038/s41598-017-01411-1] [PMID: 28469254]
[http://dx.doi.org/10.1111/imm.13001] [PMID: 30220083]
[http://dx.doi.org/10.1186/s13045-020-00917-y] [PMID: 32600443]
[http://dx.doi.org/10.3389/fimmu.2019.01638] [PMID: 31379838]
[http://dx.doi.org/10.1038/s41416-018-0313-5] [PMID: 30382166]
[http://dx.doi.org/10.1038/16717] [PMID: 9930702]
[http://dx.doi.org/10.1002/eji.200636661] [PMID: 17549732]
[http://dx.doi.org/10.4049/jimmunol.165.9.5035] [PMID: 11046032]
[http://dx.doi.org/10.1016/j.jim.2015.04.015] [PMID: 25956037]
[http://dx.doi.org/10.1016/j.jaci.2010.05.022] [PMID: 20624644]
[http://dx.doi.org/10.1158/0008-5472.CAN-10-1379] [PMID: 21098714]
[http://dx.doi.org/10.1080/14728222.2018.1444753] [PMID: 29468927]
[http://dx.doi.org/10.1002/jlb.64.4.503] [PMID: 9766631]
[http://dx.doi.org/10.1111/j.1600-065X.2009.00766.x] [PMID: 19426222]
[http://dx.doi.org/10.1053/j.seminoncol.2010.09.013] [PMID: 21074068]
[http://dx.doi.org/10.1038/srep34825] [PMID: 27708417]
[http://dx.doi.org/10.1038/s41598-017-18327-5] [PMID: 29311633]
[http://dx.doi.org/10.1111/j.1600-065X.2011.01055.x] [PMID: 22017431]
[http://dx.doi.org/10.1136/esmoopen-2019-000573] [PMID: 32392177]
[http://dx.doi.org/10.1016/j.celrep.2018.06.052] [PMID: 30021159]
[http://dx.doi.org/10.21037/tlcr.2019.08.15] [PMID: 31555511]
[http://dx.doi.org/10.1182/blood.V92.9.3338] [PMID: 9787171]
[http://dx.doi.org/10.2353/ajpath.2010.100353] [PMID: 20952591]
[http://dx.doi.org/10.1159/000505975] [PMID: 32097938]
[http://dx.doi.org/10.3389/fonc.2015.00034] [PMID: 25763356]
[http://dx.doi.org/10.1016/j.jaci.2018.11.053] [PMID: 30738171]
[http://dx.doi.org/10.1002/eji.200324804] [PMID: 14991590]
[http://dx.doi.org/10.1007/978-0-387-89520-8_11] [PMID: 19760073]
[http://dx.doi.org/10.1002/eji.200425818] [PMID: 15770698]
[http://dx.doi.org/10.1038/nri1867] [PMID: 16868552]
[http://dx.doi.org/10.1016/j.molimm.2007.05.013] [PMID: 17602748]
[http://dx.doi.org/10.4049/jimmunol.1001912] [PMID: 21076066]
[http://dx.doi.org/10.4049/jimmunol.1403076] [PMID: 26423152]
[http://dx.doi.org/10.1038/s41379-020-0550-z] [PMID: 32350416]
[http://dx.doi.org/10.1371/journal.pone.0010436] [PMID: 20454651]
[http://dx.doi.org/10.1007/s00262-010-0866-5] [PMID: 20480365]
[http://dx.doi.org/10.1016/j.ejca.2016.06.028] [PMID: 27591414]
[http://dx.doi.org/10.1158/0008-5472.CAN-16-1439] [PMID: 28611044]
[http://dx.doi.org/10.1111/j.1600-065X.2009.00782.x] [PMID: 19426221]
[http://dx.doi.org/10.4049/jimmunol.178.2.671]
[http://dx.doi.org/10.1016/0167-5699(94)90269-0] [PMID: 7524518]
[PMID: 15242934]
[http://dx.doi.org/10.3390/ijms10093900] [PMID: 19865524]
[http://dx.doi.org/10.1136/esmoopen-2019-000510] [PMID: 31275618]
[http://dx.doi.org/10.1007/s13277-014-2407-x] [PMID: 25117071]
[http://dx.doi.org/10.1038/sj.leu.2402090] [PMID: 11368354]
[http://dx.doi.org/10.1007/978-0-387-70630-6_11]
[http://dx.doi.org/10.3109/08830185.2012.698337] [PMID: 22804571]
[http://dx.doi.org/10.1158/1078-0432.CCR-06-1893]
[http://dx.doi.org/10.1073/pnas.92.24.11249] [PMID: 7479974]
[http://dx.doi.org/10.1016/j.coi.2005.04.004] [PMID: 15886117]
[http://dx.doi.org/10.1084/jem.20030916] [PMID: 14581610]
[http://dx.doi.org/10.1158/0008-5472.CAN-11-2791] [PMID: 22628427]
[http://dx.doi.org/10.1080/2162402X.2018.1440167] [PMID: 29900042]
[http://dx.doi.org/10.1046/j.1365-2141.2003.04069.x] [PMID: 12542479]
[http://dx.doi.org/10.1038/bcj.2017.55] [PMID: 28649984]
[http://dx.doi.org/10.1016/j.ccell.2017.11.001] [PMID: 29198913]
[http://dx.doi.org/10.1016/j.pharmthera.2015.07.007] [PMID: 26213107]
[http://dx.doi.org/10.1186/2162-3619-1-36] [PMID: 23210908]
[http://dx.doi.org/10.3109/10428199509059636] [PMID: 8528044]
[http://dx.doi.org/10.1161/01.RES.0000070111.98158.6C] [PMID: 12676820]
[http://dx.doi.org/10.1038/s41591-019-0737-3] [PMID: 31959992]
[http://dx.doi.org/10.3389/fonc.2019.01237] [PMID: 31824840]
[http://dx.doi.org/10.1172/JCI39748] [PMID: 20237408]
[PMID: 27930631]
[PMID: 27186412]
[http://dx.doi.org/10.1016/j.autrev.2010.12.002] [PMID: 21167321]
[PMID: 12582023]
[http://dx.doi.org/10.1007/978-1-60327-811-9_1] [PMID: 19381943]
[http://dx.doi.org/10.5483/BMBRep.2012.45.12.236] [PMID: 23261052]
[http://dx.doi.org/10.1111/cas.12650] [PMID: 25726868]
[http://dx.doi.org/10.1038/74704] [PMID: 10742152]
[http://dx.doi.org/10.1016/j.trecan.2017.07.001] [PMID: 28867165]
[http://dx.doi.org/10.1016/1044-579X(95)90001-2] [PMID: 8938270]
[PMID: 11280777]
[http://dx.doi.org/10.1097/PPO.0b013e3181eb3343] [PMID: 20693847]
[http://dx.doi.org/10.1177/1178646917691938] [PMID: 28469468]
[http://dx.doi.org/10.3390/vaccines3030703] [PMID: 26378585]
[http://dx.doi.org/10.3389/fimmu.2020.00249] [PMID: 32153576]
[http://dx.doi.org/10.1016/bs.ircmb.2017.07.004] [PMID: 29413890]
[http://dx.doi.org/10.1084/jem.20020121] [PMID: 12186838]
[http://dx.doi.org/10.1186/s40425-018-0351-9] [PMID: 29921320]
[http://dx.doi.org/10.1099/vir.0.053124-0] [PMID: 23580425]
[http://dx.doi.org/10.1111/cas.13560] [PMID: 29498788]
[http://dx.doi.org/10.7150/jca.31727] [PMID: 31258785]
[http://dx.doi.org/10.1186/s40425-015-0094-9] [PMID: 26674411]
[http://dx.doi.org/10.1007/978-3-319-67577-0_9] [PMID: 29275469]
[http://dx.doi.org/10.7150/ijms.47384] [PMID: 33390778]
[http://dx.doi.org/10.1155/2015/327470] [PMID: 26583100]