lag3 is a member of the immunoglobulin superfamily ( igsf ) and exerts a wide variety of biologic impacts on t cell function.21 lag3 is expressed on cell membranes of natural killer cells ( nk),21 b cells,22 tumorinfiltrating lymphocytes ( til ) , a subset of t cells,23 and dendritic cells ( dc)24 , 25 .
the lag3 gene encompasses 8 exons , and the cdna encodes a 498 amino acid membrane protein .
human lag3 is highly homologous with both murine ( 70% ) and pig ( 78% ) lag3.21 , 26 
  lag3 is closely related to cd 4.27 lag3 is located on the human chromosome 12 ( 12p13.32 ) adjacent to the cd 4 gene , and its sequence is approximately 20% identical to cd 4.21 the lag3 protein binds a nonholomorphic region of major histocompatibility complex 2 ( mhc class ii ) with greater affinity than cd 4.28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 lag3 is one of the various immunecheckpoint receptors that are coordinately upregulated on both regulatory t cells ( tregs ) and anergic t cells , and the simultaneous blockade of these receptors can result in an enhanced reversal of this anergic state relative to the blockade of one receptor alone.18 the lag3/mhc class ii molecule interaction leads to the downregulation of cd4 + agspecific t cell clone proliferation and cytokine secretion .
t cell mhc class ii molecules downregulate t cell proliferation following lag3 binding and suggest a role for lag3 in control of the cd4 + t cell response.31 lag3 can negatively regulated t cell proliferation , activation and homeostasis .
slag3 is a th1 activity marker in serum that can be detected by elisa.36 , 37 slag3 causes dcs to mature 38 , 39 , 40 , 41 , 42 , 43 , 44 and attack tumor cells.43 , 44 studies of the mechanisms that underlie monocyte and dc activation38 , 40 by slag3 indicate that slag3 induces protein phosphorylation in immature dc that triggers the functional maturation.38 , 39 this process requires slag3 binding with mhc class ii.28 

beyond the role it plays in a variety of autoimmune diseases , lag3 can also reduce the body 's ability to resist infection and promote chronic infection .
lag3 prevents autoimmune disorders in the eye by inducing anterior chamberassociated immune deviation.45 lag3 may regulate the functions of cd4 + and cd8 + t cells during autoimmune diabetes , and limit autoimmunity in diseaseprone environments.46 in bone marrow transplant ( bmt ) patients , lag3 can regulate cd8 + cells involved in alloreactivity , t cell proliferation and activation after bmt.47 , 48 in patients with chronic viral infection , the blockade of both pd1 and lag3 could synergistically activate t cell responses and control the virus.49 lag3 negatively regulates cd8 + t cells in chronic hepatitis c patients.50 in tuberculosis , slag3 is elevated both in healthy people who have been exposed to the bacteria and in tuberculosis patients with good prognoses,51 indicating that slag3 could modulate an antibacterial immune response in mycobacterium tuberculosis.52 in acquired immune deficiency , high expression of lag3 was correlated with impaired invariant natural killer t cell cytokine production for the duration of chronic human immunodeficiency virus ( hiv)1 infection and treatment.53 , 54 targeting the lag3 pathway has an immune regulatory effect and can enhance immune reconstitution in hivinfected patients.55 

vital preclinical studies have demonstrated that lag3 antibodies have potential for cancer immunotherapy ( table 1 ) .
dc , dendritic cells ; lag3 , lymphocyteactivation gene3 ; slag3 , soluble lag3 ; til , tumorinfiltrating lymphocytes .
lag3 may be an even more promising target in cancer immunotherapy , because antilag3 antibodies can activate t effector cells and affect tregs function.67 many companies are now focusing on the lag3 immune checkpoint in their search for novel approaches to treat malignant tumors and autoimmune disorders , many of which are now in clinical development ( table 2 ) . clinical trials with lag3
lag3 and ctla4 function similarly.19 , 68 , 69 ctla4 inhibits t cell activation , suppresses t cell receptor signaling , and promotes cell cycle arrest.70 activated lag3/ t cells extend cell cycle progression and increase t cell death .
the similarity of function between lag3 and ctla4 may be related to some intersection in their signal transduction pathways .
tetravalent ctla4ig and lag3ig could have a synergistic effect in preventing acute graftversushost disease ( gvhd ) .
lag3 has synergistic action with pd1/pdl1.20 , 48 , 72 lag3 and pd1 are critical for the prevention of autoimmunity .
their synergistic function reverses autoimmune disease.19 a deficiency of lag3 and pd1 caused lethal myocarditis in a mouse model .
the respective ligand receptor interactions between pdl1 and lag3 , together with the molecules themselves , synergistically inhibit t cell responses during persistent plasmodium .
blockade of pdl1 and lag3 activated cd 4 + t cells , increased helper t cells and b cells , enhanced protective antibodies and rapidly cleared bloodstage malaria in mice.73 in chronic viral infection , lag3 and pd1 maintain cd8 + t cell exhaustion.18 , 49 
 in vivo research has shown that the blockade of pd1 and lag3 pathways can activate t cells to achieve better viral control compared to either blockade alone.49 coexpression of lag3 and pd1 can induce greater t cell exhaustion and more severe infection.23 pd1 and lag3 signaling pathways can inhibit cd 8 by antigen and cytokine signaling.18 in ovarian cancer , cd8 + til could be negatively regulated by lag3 and pd1 .
cd8+lag3+pd1 + t cells significantly reduced ifn/tnf. blockade of both lag3 and pd1 could increase specific cd8 + t cells producing cytokine.59 it was also reported that lag3 and pd1 synergistically regulate tcell function , blunting the antitumor immune response .
lag3pdcd1 mice developed an early onset , lethal autoimmune condition , but not a single knockout or wildtype mice .
cytokine analysis revealed high levels of ifn , tnf and mcp1 in the serum of lag3pdcd1 recipients but not a single knockout or wildtype control recipient .
although ctla4 , pd1 and lag3 are all negative regulators expressed during tcell activation , high level , dual lag3/pd1 expression is largely restricted to infiltrating til .
thus , lag3/pd1 combinatorial immunotherapy may promote the tumorspecific responses relative to nonspecific or selfantigenspecific immune responses and , thus , may be less toxic than the ctla4 blockade.20 dual antilag3 and antipd1 antibody therapy has a better prognosis than single antibody therapy .
dual knockout mice survive longer than single knockout mice . the strong synergy between the pd1 and lag3 inhibitory pathways
another important immune checkpoint , lag3 , which is closely related to cd4 , can regulate t cell proliferation , activation and homeostasis .
lag3 plays an important role in a variety of autoimmune diseases and promotes chronic infection and cancer .
the authors report no conflicts of interest . the authors alone are responsible for the content and writing of the paper .
 immunotherapy has recently become widely used in lung cancer . 
 many oncologists are focused on cytotoxic t lymphocyte antigen4 ( ctla4 ) , programmed cell death ligand1 ( pdl1 ) and programmed cell death1 ( pd1 ) . 
 immunotherapy targeting the pd1/pdl1 checkpoints has shown promising efficacy in nonsmall cell lung cancer ( nsclc ) , but questions remain to be answered . among them is whether the simultaneous inhibition of other checkpoints could improve outcomes . 
 lymphocyteactivation gene3 ( lag3 ) is another vital checkpoint that may have a synergistic interaction with pd1/pdl1 . 
 here we review the lag3 function in cancer , clinical trials with agents targeting lag3 and the correlation of lag3 with other checkpoints . 