首页科学与技术科学纪事Immune checkpoint inhibitors: A strategy to tackle cancer?
Immune checkpoint inhibitors: A strategy to tackle cancer?
2019-07-16
Our immune system is constantlyon the lookout for pathogens and, once it encounters one,it mounts a strategic attack to fight it: it is the so-calledimmune response.To minimize the potential collateraldamage to healthy cells and tissues though, this responseneeds to be tuned down.(1, 2) And that is precisely the roleof inhibitory immune checkpoints, aplethora of molecules naturally expressed both on Tcells and antigen-presenting cells that maintains self-tolerance and limitstissue damage byrecognizing ligands expressed on self-tissues.(3) In the past 30 years, a broad range of immune checkpoint moleculeshave been identified, including cytotoxicT-lymphocyte-associated antigen 4 (CTLA-4) and programmedcell death protein 1 (PD-1)whose discoveries have earned James P.Allison and Tasuku Honjo the Nobel Prize in medicine in 2018.Both proteins act as negative regulators of Tcell activation, thereby preventingunwanted immune responses.(4, 5, 6, 7, 8)
Immune checkpoints are also expressed on many tumor cells,allowingthem to cleverly evade host immune responseand divide uncontrollably.(9) Interestingly, several invivo studies have demonstrated thatantibodiesdirected against key immune checkpoints suchas PD-1 and CTLA-4 inhibit their function,therebyallowing the elimination of certain tumor cells.(2, 10, 11, 12)These findings haveprovided a rationale for targeting immune checkpointsto enhance antitumor immunity, andrevolutionized cancer therapy. Indeed, several immunecheckpoint molecules, including PD-1 andCTLA-4,have been approved by the Food and DrugAdministration (FDA) for treating certain types ofcancers, while others are under clinical trials.(12) These new immunotherapies, knownas checkpoint inhibitors, represent ahighlyeffective treatment forsolid cancers, such as metastaticmelanomas, non-small-cell lung carcinomas andliver cancer, and offer patients a durable remission fromdiseases whose outcomeswere previously invariably terminal.(12, 13, 14)
Accumulating evidence suggests that only a number of patients benefitfrom checkpoint inhibitors,and that a fraction of those developa wide range of severe autoimmune responses.(3, 13, 15, 16) These observationshave given rise to the need to developpredictive biomarkers todifferentiatebetweenresponders and non-responders,avoid any adverse effect,and facilitate the decision-making process to select the bestimmune checkpointinhibitor-based therapy for each patient.(12, 17) Ongoing clinical studies have already identified some of them (e.g.,immune cell counts, neoantigens, gene mutations)(12) and others areunderway,which could represent an important firststep toward personalized medicine incancer treatment.
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