Update on lymphocyte-activation gene 3 (LAG-3) in cancers: from biological properties to clinical applications.
Journal
Chinese medical journal
ISSN: 2542-5641
Titre abrégé: Chin Med J (Engl)
Pays: China
ID NLM: 7513795
Informations de publication
Date de publication:
20 May 2022
20 May 2022
Historique:
pubmed:
17
2
2022
medline:
3
8
2022
entrez:
16
2
2022
Statut:
epublish
Résumé
Immunotherapy that targets checkpoints, especially programmed cell death protein 1 and programmed cell death ligand 1, has revolutionized cancer therapy regimens. The overall response rate to mono-immunotherapy, however, is limited, emphasizing the need to potentiate the efficacy of these regimens. The functions of immune cells are modulated by multiple stimulatory and inhibitory molecules, including lymphocyte activation gene 3 (LAG-3). LAG-3 is co-expressed together with other inhibitory checkpoints and plays key roles in immune suppression. Increasing evidence, particularly in the last 5 years, has shown the potential of LAG-3 blockade in anti-tumor immunity. This review provides an update on the biological properties and clinical applications of LAG-3 in cancers.
Identifiants
pubmed: 35170503
doi: 10.1097/CM9.0000000000001981
pii: 00029330-202205200-00009
pmc: PMC9337260
doi:
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
1203-1212Informations de copyright
Copyright © 2022 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.
Références
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥50. J Clin Oncol 2021; 39:2339–2349. doi: 10.1200/jco.21.00174.
doi: 10.1200/jco.21.00174
Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol 2015; 33:1974–1982. doi: 10.1200/jco.2014.59.4358.
doi: 10.1200/jco.2014.59.4358
Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373:123–135. doi: 10.1056/NEJMoa1504627.
doi: 10.1056/NEJMoa1504627
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373:1627–1639. doi: 10.1056/NEJMoa1507643.
doi: 10.1056/NEJMoa1507643
Liu Y, Chen P, Wang H, Wu S, Zhao S, He Y, et al. The landscape of immune checkpoints expression in non-small cell lung cancer: a narrative review. Transl Lung Cancer Res 2021; 10:1029–1038. doi: 10.21037/tlcr-20-1019.
doi: 10.21037/tlcr-20-1019
Chen P, Zhao L, Wang H, Zhang L, Zhang W, Zhu J, et al. Human leukocyte antigen class II-based immune risk model for recurrence evaluation in stage I-III small cell lung cancer. J Immunother Cancer 2021; 9:e002554doi: 10.1136/jitc-2021-002554.
doi: 10.1136/jitc-2021-002554
He Y, Rivard CJ, Rozeboom L, Yu H, Ellison K, Kowalewski A, et al. Lymphocyte-activation gene-3, an important immune checkpoint in cancer. Cancer Sci 2016; 107:1193–1197. doi: 10.1111/cas.12986.
doi: 10.1111/cas.12986
Ruffo E, Wu RC, Bruno TC, Workman CJ, Vignali DAA. Lymphocyte-activation gene 3 (LAG3): the next immune checkpoint receptor. Semin Immunol 2019; 42:101305doi: 10.1016/j. smim.2019.101305.
doi: 10.1016/j.
Qi Y, Chen L, Liu Q, Kong X, Fang Y, Wang J. Research progress concerning dual blockade of lymphocyte-activation gene 3 and programmed death-1/programmed death-1 ligand-1 blockade in cancer immunotherapy: preclinical and clinical evidence of this potentially more effective immunotherapy strategy. Front Immunol 2020; 11:563258doi: 10.3389/fimmu.2020.563258.
doi: 10.3389/fimmu.2020.563258
Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med 1990; 171:1393–1405. doi: 10.1084/jem.171.5.1393.
doi: 10.1084/jem.171.5.1393
Li N, Wang Y, Forbes K, Vignali KM, Heale BS, Saftig P, et al. Metalloproteases regulate T-cell proliferation and effector function via LAG-3. EMBO J 2007; 26:494–504. doi: 10.1038/sj. emboj.7601520.
doi: 10.1038/sj.
Workman CJ, Vignali DA. The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells. Eur J Immunol 2003; 33:970–979. doi: 10.1002/eji.200323382.
doi: 10.1002/eji.200323382
Hemon P, Jean-Louis F, Ramgolam K, Brignone C, Viguier M, Bachelez H, et al. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis. J Immunol 2011; 186:5173–5183. doi: 10.4049/jimmunol. 1002050.
doi: 10.4049/jimmunol.
Lythgoe MP, Liu DSK, Annels NE, Krell J, Frampton AE. Gene of the month: lymphocyte-activation gene 3 (LAG-3). J Clin Pathol 2021; 74:543–547. doi: 10.1136/jclinpath-2021-207517.
doi: 10.1136/jclinpath-2021-207517
Avice MN, Sarfati M, Triebel F, Delespesse G, Demeure CE. Lymphocyte activation gene-3, a MHC class II ligand expressed on activated T cells, stimulates TNF-alpha and IL-12 production by monocytes and dendritic cells. J Immunol 1999; 162:2748–2753.
Andreae S, Piras F, Burdin N, Triebel F. Maturation and activation of dendritic cells induced by lymphocyte activation gene-3 (CD223). J Immunol 2002; 168:3874–3880. doi: 10.4049/jimmu-nol.168.8.3874.
doi: 10.4049/jimmu-nol.168.8.3874
Kouo T, Huang L, Pucsek AB, Cao M, Solt S, Armstrong T, et al. Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunol Res 2015; 3:412–423. doi: 10.1158/2326-6066.Cir-14-0150.
doi: 10.1158/2326-6066.Cir-14-0150
Xu F, Liu J, Liu D, Liu B, Wang M, Hu Z, et al. LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res 2014; 74:3418–3428. doi: 10.1158/0008-5472.Can-13-2690.
doi: 10.1158/0008-5472.Can-13-2690
Wang J, Sanmamed MF, Datar I, Su TT, Ji L, Sun J, et al. Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell 2019; 176:334.e12–347.e12doi: 10.1016/j.cell. 2018.11.010.
doi: 10.1016/j.cell.
Qian W, Zhao M, Wang R, Li H. Fibrinogen-like protein 1 (FGL1): the next immune checkpoint target. J Hematol Oncol 2021; 14:147doi: 10.1186/s13045-021-01161-8.
doi: 10.1186/s13045-021-01161-8
Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, et al. Pathological a-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 2016; 353:aah3374doi: 10.1126/science.aah3374.
doi: 10.1126/science.aah3374
Chocarro L, Blanco E, Zuazo M, Arasanz H, Bocanegra A, Fernández-Rubio L, et al. Understanding LAG-3 signaling. Int J Mol Sci 2021; 22:5282doi: 10.3390/ijms22105282.
doi: 10.3390/ijms22105282
Saleh R, Toor SM, Sasidharan Nair V, Elkord E. Role of epigenetic modifications in inhibitory immune checkpoints in cancer development and progression. Front Immunol 2020; 11:1469doi: 10.3389/fimmu.2020.01469.
doi: 10.3389/fimmu.2020.01469
Klümper N, Ralser DJ, Bawden EG, Landsberg J, Zarbl R, Kristiansen G, et al. (LAG-3, CD223) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma. J Immunother Cancer 2020; 8:e000552doi: 10.1136/jitc-2020-000552.
doi: 10.1136/jitc-2020-000552
Fröhlich A, Sirokay J, Fietz S, Vogt TJ, Dietrich J, Zarbl R, et al. Molecular, clinicopathological, and immune correlates of LAG3 promoter DNA methylation in melanoma. EBioMedicine 2020; 59:102962doi: 10.1016/j.ebiom.2020.102962.
doi: 10.1016/j.ebiom.2020.102962
Sasidharan Nair V, El Salhat H, Taha RZ, John A, Ali BR, Elkord E. DNA methylation and repressive H3K9 and H3K27 trimethy-lation in the promoter regions of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and PD-L1 genes in human primary breast cancer. Clin Epigenetics 2018; 10:78doi: 10.1186/s13148-018-0512-1.
doi: 10.1186/s13148-018-0512-1
Elashi AA, Sasidharan Nair V, Taha RZ, Shaath H, Elkord E. DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients. Oncoimmunology 2019; 8:e1542918doi: 10.1080/2162402x.2018.1542918.
doi: 10.1080/2162402x.2018.1542918
Yi T, Zhang Y, Ng DM, Xi Y, Ye M, Cen L, et al. Regulatory network analysis of mutated genes based on multi-omics data reveals the exclusive features in tumor immune microenvironment between left-sided and right-sided colon cancer. Front Oncol 2021; 11:685515doi: 10.3389/fonc.2021.685515.
doi: 10.3389/fonc.2021.685515
Wang Y, Wang J, Meng J, Jiang H, Zhao J, Qian H, et al. Epigenetic modification mediates the increase of LAG-3(+) T cells in chronic osteomyelitis. Inflammation 2017; 40:414–421. doi: 10.1007/s10753-016-0486-0.
doi: 10.1007/s10753-016-0486-0
Zeng Z, Wei F, Ren X. Exhausted T cells and epigenetic status. Cancer Biol Med 2020; 17:923–936. doi: 10.20892/j.issn.2095-3941.2020.0338.
doi: 10.20892/j.issn.2095-3941.2020.0338
Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, et al. TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature 2019; 571:211–218. doi: 10.1038/s41586-019-1325-x.
doi: 10.1038/s41586-019-1325-x
Ames RY, Ting LM, Gendlina I, Kim K, Macian F. The transcription factor NFAT1 participates in the induction of CD4(+) T cell functional exhaustion during plasmodium yoelii infection. Infect Immun 2017; 85:e00364–e417. doi: 10.1128/iai.00364-17.
doi: 10.1128/iai.00364-17
Chen J, López-Moyado IF, Seo H, Lio CJ, Hempleman LJ, Sekiya T, et al. NR4A transcription factors limit CAR T cell function in solid tumours. Nature 2019; 567:530–534. doi: 10.1038/s41586-019-0985-x.
doi: 10.1038/s41586-019-0985-x
Williams JB, Horton BL, Zheng Y, Duan Y, Powell JD, Gajewski TF. The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment. J Exp Med 2017; 214:381–400. doi: 10.1084/jem.20160485.
doi: 10.1084/jem.20160485
Okamura T, Fujio K, Shibuya M, Sumitomo S, Shoda H, Sakaguchi S, et al. CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2. Proc Natl Acad Sci USA 2009; 106:13974–13979. doi: 10.1073/pnas.0906872106.
doi: 10.1073/pnas.0906872106
Rudd CE, Chanthong K, Taylor A. Small molecule inhibition of GSK-3 specifically inhibits the transcription of inhibitory co-receptor LAG-3 for enhanced anti-tumor immunity. Cell Rep 2020; 30:2075.e4–2082.e4doi: 10.1016/j.celrep.2020.01.076.
doi: 10.1016/j.celrep.2020.01.076
Zheng Y, Song A, Zhou Y, Zhong Y, Zhang W, Wang C, et al. Identification of extracellular vesicles-transported miRNAs in Erlotinib-resistant head and neck squamous cell carcinoma. J Cell Commun Signal 2020; 14:389–402. doi: 10.1007/s12079-020-00546-7.
doi: 10.1007/s12079-020-00546-7
Yan G, An Y, Xu B, Wang N, Sun X, Sun M. Potential impact of ALKBH5 and YTHDF1 on tumor immunity in colon adenocarcinoma. Front Oncol 2021; 11:670490doi: 10.3389/fonc.2021.670490.
doi: 10.3389/fonc.2021.670490
Bae J, Lee SJ, Park CG, Lee YS, Chun T. Trafficking of LAG-3 to the surface on activated T cells via its cytoplasmic domain and protein kinase C signaling. J Immunol 2014; 193:3101–3112. doi: 10.4049/jimmunol.1401025.
doi: 10.4049/jimmunol.1401025
Li N, Jilisihan B, Wang W, Tang Y, Keyoumu S. Soluble LAG3 acts as a potential prognostic marker of gastric cancer and its positive correlation with CD8+T cell frequency and secretion of IL-12 and INF-g in peripheral blood. Cancer Biomark 2018; 23:341–351. doi: 10.3233/cbm-181278.
doi: 10.3233/cbm-181278
Botticelli A, Zizzari IG, Scagnoli S, Pomati G, Strigari L, Cirillo A, et al. The role of soluble LAG3 and soluble immune checkpoints profile in advanced head and neck cancer: a pilot study. J Pers Med 2021; 11:651doi: 10.3390/jpm11070651.
doi: 10.3390/jpm11070651
Wang Q, Zhang J, Tu H, Liang D, Chang DW, Ye Y, et al. Soluble immune checkpoint-related proteins as predictors of tumor recurrence, survival, and T cell phenotypes in clear cell renal cell carcinoma patients. J Immunother Cancer 2019; 7:334doi: 10.1186/s40425-019-0810-y.
doi: 10.1186/s40425-019-0810-y
Triebel F, Hacene K, Pichon MF. A soluble lymphocyte activation gene-3 (sLAG-3) protein as a prognostic factor in human breast cancer expressing estrogen or progesterone receptors. Cancer Lett 2006; 235:147–153. doi: 10.1016/j.canlet.2005.04.015.
doi: 10.1016/j.canlet.2005.04.015
Solinas C, Migliori E, De Silva P, Willard-Gallo K. LAG3: the biological processes that motivate targeting this immune checkpoint molecule in human cancer. Cancers (Basel) 2019; 11:1213doi: 10.3390/cancers11081213.
doi: 10.3390/cancers11081213
Long L, Zhang X, Chen F, Pan Q, Phiphatwatchara P, Zeng Y, et al. The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy. Genes Cancer 2018; 9:176–189. doi: 10.18632/genesandcancer.180.
doi: 10.18632/genesandcancer.180
Westergaard MCW, Milne K, Pedersen M, Hasselager T, Olsen LR, Anglesio MS, et al. Changes in the tumor immune microenvironment during disease progression in patients with ovarian cancer. Cancers (Basel) 2020; 12:3828doi: 10.3390/cancers12123828.
doi: 10.3390/cancers12123828
Huard B, Prigent P, Pagès F, Bruniquel D, Triebel F. T cell major histocompatibility complex class II molecules down-regulate CD4 + T cell clone responses following LAG-3 binding. Eur J Immunol 1996; 26:1180–1186. doi: 10.1002/eji.1830260533.
doi: 10.1002/eji.1830260533
Workman CJ, Dugger KJ, Vignali DA. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J Immunol 2002; 169:5392–5395. doi: 10.4049/jimmunol.169.10.5392.
doi: 10.4049/jimmunol.169.10.5392
He Y, Yu H, Rozeboom L, Rivard CJ, Ellison K, Dziadziuszko R, et al. LAG-3 protein expression in non-small cell lung cancer and its relationship with PD-1/PD-L1 and tumor-infiltrating lymphocytes. J Thorac Oncol 2017; 12:814–823. doi: 10.1016/j. jtho.2017.01.019.
doi: 10.1016/j.
Zhou J, Yu X, Hou L, Zhao J, Zhou F, Chu X, et al. Epidermal growth factor receptor tyrosine kinase inhibitor remodels tumor microenvironment by upregulating LAG-3 in advanced non-small-cell lung cancer. Lung Cancer 2021; 153:143–149. doi: 10.1016/j. lungcan.2021.01.010.
doi: 10.1016/j.
Zhang Y, Liu YD, Luo YL, Liu BL, Huang QT, Wang F, et al. Prognostic value of lymphocyte activation gene-3 (LAG-3) expression in esophageal squamous cell carcinoma. J Cancer 2018; 9:4287–4293. doi: 10.7150/jca.26949.
doi: 10.7150/jca.26949
Wang W, Chen D, Zhao Y, Zhao T, Wen J, Mao Y, et al. Characterization of LAG-3, CTLA-4, and CD8(+) TIL density and their joint influence on the prognosis of patients with esophageal squamous cell carcinoma. Ann Transl Med 2019; 7:776doi: 10.21037/atm.2019.11.38.
doi: 10.21037/atm.2019.11.38
Giraldo NA, Becht E, Pages F, Skliris G, Verkarre V, Vano Y, et al. Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin Cancer Res 2015; 21:3031–3040. doi: 10.1158/1078-0432.Ccr-14-2926.
doi: 10.1158/1078-0432.Ccr-14-2926
Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A 2010; 107:7875–7880. doi: 10.1073/pnas.1003345107.
doi: 10.1073/pnas.1003345107
Wu S, Shi X, Wang J, Wang X, Liu Y, Luo Y, et al. Triple-negative breast cancer: intact mismatch repair and partial co-expression of PD-L1 and LAG-3. Front Immunol 2021; 12:561793doi: 10.3389/fimmu.2021.561793.
doi: 10.3389/fimmu.2021.561793
Lichtenegger FS, Rothe M, Schnorfeil FM, Deiser K, Krupka C, Augsberger C, et al. Targeting LAG-3 and PD-1 to enhance T cell activation by antigen-presenting cells. Front Immunol 2018; 9:385doi: 10.3389/fimmu.2018.00385.
doi: 10.3389/fimmu.2018.00385
Wang J, Wei W, Tang Q, Lu L, Luo Z, Li W, et al. Oxysophocarpine suppresses hepatocellular carcinoma growth and sensitizes the therapeutic blockade of anti-Lag-3 via reducing FGL1 expression. Cancer Med 2020; 9:7125–7136. doi: 10.1002/cam4.3151.
doi: 10.1002/cam4.3151
Zhai W, Zhou X, Wang H, Li W, Chen G, Sui X, et al. A novel cyclic peptide targeting LAG-3 for cancer immunotherapy by activating antigen-specific CD8(+) Tcell responses. Acta Pharm Sin B 2020; 10:1047–1060. doi: 10.1016/j.apsb.2020.01.005.
doi: 10.1016/j.apsb.2020.01.005
Wang M, Du Q, Jin J, Wei Y, Lu Y, Li Q. LAG3 and its emerging role in cancer immunotherapy. Clin Transl Med 2021; 11:e365doi: 10.1002/ctm2.365.
doi: 10.1002/ctm2.365
Liang B, Workman C, Lee J, Chew C, Dale BM, Colonna L, et al. Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J Immunol 2008; 180:5916–5926. doi: 10.4049/jimmunol.180.9.5916.
doi: 10.4049/jimmunol.180.9.5916
Roncarolo MG, Battaglia M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol 2007; 7:585–598. doi: 10.1038/nri2138.
doi: 10.1038/nri2138
Okamura T, Sumitomo S, Morita K, Iwasaki Y, Inoue M, Nakachi S, et al. TGF-β3-expressing CD4+CD25(−)LAG3+ regulatory T cells control humoral immune responses. Nat Commun 2015; 6:6329doi: 10.1038/ncomms7329.
doi: 10.1038/ncomms7329
Fujio K, Yamamoto K, Okamura T. Overview of LAG-3-expressing, IL-10-producing regulatory T cells. Curr Top Microbiol Immunol 2017; 410:29–45. doi: 10.1007/82_2017_59.
doi: 10.1007/82_2017_59
Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med 2013; 19:739–746. doi: 10.1038/nm.3179.
doi: 10.1038/nm.3179
Pedroza-Gonzalez A, Zhou G, Vargas-Mendez E, Boor PP, Mancham S, Verhoef C, et al. Tumor-infiltrating plasmacytoid dendritic cells promote immunosuppression by Tr1 cells in human liver tumors. Oncoimmunology 2015; 4:e1008355doi: 10.1080/2162402x.2015.1008355.
doi: 10.1080/2162402x.2015.1008355
Alfarra H, Weir J, Grieve S, Reiman T. Targeting NK cell inhibitory receptors for precision multiple myeloma immunotherapy. Front Immunol 2020; 11:575609doi: 10.3389/fimmu.2020. 575609.
doi: 10.3389/fimmu.2020.
Huard B, Tournier M, Triebel F. LAG-3 does not define a specific mode of natural killing in human. Immunol Lett 1998; 61:109–112. doi: 10.1016/s0165-2478(97)00170-3.
doi: 10.1016/s0165-2478(97)00170-3
Almeida JS, Couceiro P, López-Sejas N, Alves V, Ružicková L, Tarazona R, et al. NKT-like (CD3+CD56+) cells in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Front Immunol 2019; 10:2493doi: 10.3389/fimmu.2019.02493.
doi: 10.3389/fimmu.2019.02493
Reizis B. Plasmacytoid dendritic cells: development, regulation, and function. Immunity 2019; 50:37–50. doi: 10.1016/j.immuni. 2018.12.027.
doi: 10.1016/j.immuni.
Workman CJ, Wang Y, El Kasmi KC, Pardoll DM, Murray PJ, Drake CG, et al. LAG-3 regulates plasmacytoid dendritic cell homeostasis. J Immunol 2009; 182:1885–1891. doi: 10.4049/jimmunol.0800185.
doi: 10.4049/jimmunol.0800185
Lino AC, Dang VD, Lampropoulou V, Welle A, Joedicke J, Pohar J, et al. LAG-3 inhibitory receptor expression identifies immuno-suppressive natural regulatory plasma cells. Immunity 2018; 49:120–133.e9doi: 10.1016/j.immuni.2018.06.007.
doi: 10.1016/j.immuni.2018.06.007
Maruhashi T, Sugiura D, Okazaki IM, Okazaki T. LAG-3: from molecular functions to clinical applications. J Immunother Cancer 2020; 8:e001014doi: 10.1136/jitc-2020-001014.
doi: 10.1136/jitc-2020-001014
Stovgaard ES, Kümler I, List-Jensen K, Roslind A, Christensen IJ, Høgdall E, et al. Prognostic and clinicopathologic associations of LAG-3 expression in triple-negative breast cancer. Appl Immu-nohistochem Mol Morphol 2022; 30:62–71. doi: 10.1097/pai.0000000000000954.
doi: 10.1097/pai.0000000000000954
Rådestad E, Klynning C, Stikvoort A, Mogensen O, Nava S, Magalhaes I, et al. Immune profiling and identification of prognostic immune-related risk factors in human ovarian cancer. Oncoimmunology 2019; 8:e1535730doi: 10.1080/2162402x.2018.1535730.
doi: 10.1080/2162402x.2018.1535730
Zelba H, Bedke J, Hennenlotter J, Mostböck S, Zettl M, Zichner T, et al. PD-1 and LAG-3 dominate checkpoint receptor-mediated T-cell inhibition in renal cell carcinoma. Cancer Immunol Res 2019; 7:1891–1899. doi: 10.1158/2326-6066.Cir-19-0146.
doi: 10.1158/2326-6066.Cir-19-0146
Whitehair R, Peres LC, Mills AM. Expression of the immune checkpoints LAG-3 and PD-L1 in high-grade serous ovarian carcinoma: relationship to tumor-associated lymphocytes and germline BRCA status. Int J Gynecol Pathol 2020; 39:558–566. doi: 10.1097/pgp.0000000000000657.
doi: 10.1097/pgp.0000000000000657
Park Y, Seo AN, Koh J, Nam SK, Kwak Y, Ahn SH, et al. Expression of the immune checkpoint receptors PD-1, LAG3, and TIM3 in the immune context of stage II and III gastric cancer by using single and chromogenic multiplex immunohistochemistry. Oncoimmunology 2021; 10:1954761doi: 10.1080/2162402x.2021.1954761.
doi: 10.1080/2162402x.2021.1954761
Zhou G, Noordam L, Sprengers D, Doukas M, Boor PPC, van Beek AA, et al. Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer. Oncoimmunology 2018; 7:e1448332doi: 10.1080/2162402x.2018.1448332.
doi: 10.1080/2162402x.2018.1448332
Liu Q, Qi Y, Zhai J, Kong X, Wang X, Wang Z, et al. Molecular and clinical characterization of LAG3 in breast cancer through 2994 samples. Front Immunol 2021; 12:599207doi: 10.3389/fimmu.2021.599207.
doi: 10.3389/fimmu.2021.599207
Sobottka B, Moch H, Varga Z. Differential PD-1/LAG-3 expression and immune phenotypes in metastatic sites of breast cancer. Breast Cancer Res 2021; 23:4doi: 10.1186/s13058-020-01380-w.
doi: 10.1186/s13058-020-01380-w
Gestermann N, Saugy D, Martignier C, Tillé L, Fuertes Marraco SA, Zettl M, et al. LAG-3 and PD-1+LAG-3 inhibition promote anti-tumor immune responses in human autologous melanoma/T cell co-cultures. Oncoimmunology 2020; 9:1736792doi: 10.1080/2162402x.2020.1736792.
doi: 10.1080/2162402x.2020.1736792
Huang RY, Francois A, McGray AR, Miliotto A, Odunsi K. Compensatory upregulation of PD-1, LAG-3, and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer. Oncoimmunology 2017; 6:e1249561doi: 10.1080/2162402x.2016.1249561.
doi: 10.1080/2162402x.2016.1249561
Yang M, Du W, Yi L, Wu S, He C, Zhai W, et al. Checkpoint molecules coordinately restrain hyperactivated effector T cells in the tumor microenvironment. Oncoimmunology 2020; 9:1708064doi: 10.1080/2162402x.2019.1708064.
doi: 10.1080/2162402x.2019.1708064
Saleh R, Toor SM, Khalaf S, Elkord E. Breast cancer cells and PD-1/PD-L1 blockade upregulate the expression of PD-1, CTLA-4, TIM-3 and LAG-3 immune checkpoints in CD4(+) T cells. Vaccines (Basel) 2019; 7:149doi: 10.3390/vaccines 7040149.
doi: 10.3390/vaccines
Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun 2016; 7:10501doi: 10.1038/ncomms10501.
doi: 10.1038/ncomms10501
Panda A, Rosenfeld JA, Singer EA, Bhanot G, Ganesan S. Genomic and immunologic correlates of LAG-3 expression in cancer. Oncoimmunology 2020; 9:1756116doi: 10.1080/2162402x.2020.1756116.
doi: 10.1080/2162402x.2020.1756116
Wang X, Zhang J, Zhou G. The CXCL11-CXCR3A axis influences the infiltration of CD274 and IDO1 in oral squamous cell carcinoma. J Oral Pathol Med 2021; 50:362–370. doi: 10.1111/jop.13130.
doi: 10.1111/jop.13130
Kim YJ, Won CH, Lee MW, Choi JH, Chang SE, Lee WJ. Correlation between tumor-associated macrophage and immune checkpoint molecule expression and its prognostic significance in cutaneous melanoma. J Clin Med 2020; 9:2500doi: 10.3390/jcm9082500.
doi: 10.3390/jcm9082500
Yang LL, Mao L, Wu H, Chen L, Deng WW, Xiao Y, et al. pDC depletion induced by CD317 blockade drives the antitumor immune response in head and neck squamous cell carcinoma. Oral Oncol 2019; 96:131–139. doi: 10.1016/j.oraloncology.2019. 07.019.
doi: 10.1016/j.oraloncology.2019.
Ohmura H, Yamaguchi K, Hanamura F, Ito M, Makiyama A, Uchino K, et al. OX40 and LAG3 are associated with better prognosis in advanced gastric cancer patients treated with anti-programmeddeath-1 antibody. Br JCancer 2020; 122:1507–1517. doi: 10.1038/s41416-020-0810-1.
doi: 10.1038/s41416-020-0810-1
Lei M, Siemers NO, Pandya D, Chang H, Sanchez T, Harbison C, et al. Analyses of PD-L1 and inflammatory gene expression association with efficacy of nivolumab ± ipilimumab in gastric cancer/gastroesophageal junction cancer. Clin Cancer Res 2021; 27:3926–3935. doi: 10.1158/1078-0432.Ccr-20-2790.
doi: 10.1158/1078-0432.Ccr-20-2790
Sangro B, Melero I, Wadhawan S, Finn RS, Abou-Alfa GK, Cheng AL, et al. Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. J Hepatol 2020; 73:1460–1469. doi: 10.1016/j.jhep.2020.07.026.
doi: 10.1016/j.jhep.2020.07.026
Datar I, Sanmamed MF, Wang J, Henick BS, Choi J, Badri T, et al. Expression analysis and significance of PD-1, LAG-3, and TIM-3 in human non-small cell lung cancer using spatially resolved and multiparametric single-cell analysis. Clin Cancer Res 2019; 25:4663–4673. doi: 10.1158/1078-0432.Ccr-18-4142.
doi: 10.1158/1078-0432.Ccr-18-4142
Lecocq Q, Awad RM, De Vlaeminck Y, De Mey W, Ertveldt T, Goyvaerts C, et al. Single-domain antibody nuclear imaging allows noninvasive quantification of LAG-3 expression by tumor-infiltrating leukocytes and predicts response of immune checkpoint blockade. J Nucl Med 2021; 62:1638–1644. doi: 10.2967/jnumed.120.258871.
doi: 10.2967/jnumed.120.258871
Bassez A, Vos H, Van Dyck L, Floris G, Arijs I, Desmedt C, et al. A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer. Nat Med 2021; 27:820–832. doi: 10.1038/s41591-021-01323-8.
doi: 10.1038/s41591-021-01323-8
Andrews LP, Somasundaram A, Moskovitz JM, Szymczak-Workman AL, Liu C, Cillo AR, et al. Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding. Sci Immunol 2020; 5:eabc2728doi: 10.1126/sciimmunol.abc2728.
doi: 10.1126/sciimmunol.abc2728
Seifert L, Plesca I, Müller L, Sommer U, Heiduk M, von Renesse J, et al. LAG-3-expressing tumor-infiltrating T cells are associated with reduced disease-free survival in pancreatic cancer. Cancers (Basel) 2021; 13:1297doi: 10.3390/cancers13061297.
doi: 10.3390/cancers13061297
Bae JY, Choi KU, Kim A, Lee SJ, Kim K, Kim JY, et al. Evaluation of immune-biomarker expression in high-grade soft-tissue sarcoma: HLA-DQA1 expression as a prognostic marker. Exp Ther Med 2020; 20:107doi: 10.3892/etm.2020.9225.
doi: 10.3892/etm.2020.9225
Arolt C, Meyer M, Ruesseler V, Nachtsheim L, Wuerdemann N, Dreyer T, et al. Lymphocyte activation gene 3 (LAG3) protein expression on tumor-infiltrating lymphocytes in aggressive and TP53-mutated salivary gland carcinomas. Cancer Immunol Immunother 2020; 69:1363–1373. doi: 10.1007/s00262-020-02551-6.
doi: 10.1007/s00262-020-02551-6
Giraldo NA, Becht E, Vano Y, Petitprez F, Lacroix L, Validire P, et al. Tumor-infiltrating and peripheral blood T-cell immunophe-notypes predict early relapse in localized clear cell renal cell carcinoma. Clin Cancer Res 2017; 23:4416–4428. doi: 10.1158/1078-0432.Ccr-16-2848.
doi: 10.1158/1078-0432.Ccr-16-2848
Deng WW, Mao L, Yu GT, Bu LL, Ma SR, Liu B, et al. LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma. Oncoimmunology 2016; 5:e1239005doi: 10.1080/2162402x.2016. 1239005.
doi: 10.1080/2162402x.2016.
Wang H, Mao L, Zhang T, Zhang L, Wu Y, Guo W, et al. Altered expression of TIM-3, LAG-3, IDO, PD-L1, and CTLA-4 during nimotuzumab therapy correlates with responses and prognosis of oral squamous cell carcinoma patients. J Oral Pathol Med 2019; 48:669–676. doi: 10.1111/jop.12883.
doi: 10.1111/jop.12883
James NE, Miller K, LaFranzo N, Lips E, Woodman M, Ou J, et al. Immune modeling analysis reveals immunologic signatures associated with improved outcomes in high grade serous ovarian cancer. Front Oncol 2021; 11:622182doi: 10.3389/fonc.2021.622182.
doi: 10.3389/fonc.2021.622182
Tu L, Guan R, Yang H, Zhou Y, Hong W, Ma L, et al. Assessment of the expression of the immune checkpoint molecules PD-1, CTLA4, TIM-3 and LAG-3 across different cancers in relation to treatment response, tumor-infiltrating immune cells and survival. Int J Cancer 2020; 147:423–439. doi: 10.1002/ijc.32785.
doi: 10.1002/ijc.32785
Gebauer F, Krämer M, Bruns C, Schlößer HA, Thelen M, Lohneis P, et al. Lymphocyte activation gene-3 (LAG3) mRNA and protein expression on tumour infiltrating lymphocytes (TILs) in oesophageal adenocarcinoma. J Cancer Res Clin Oncol 2020; 146:2319–2327. doi: 10.1007/s00432-020-03295-7.
doi: 10.1007/s00432-020-03295-7
Hald SM, Rakaee M, Martinez I, Richardsen E, Al-Saad S, Paulsen EE, et al. LAG-3 in non-small-cell lung cancer: expression in primary tumors and metastatic lymph nodes is associated with improved survival. Clin Lung Cancer 2018; 19:249–259.e2doi: 10.1016/j.cllc.2017.12.001.
doi: 10.1016/j.cllc.2017.12.001
Al-Badran SS, Grant L, Campo MV, Inthagard J, Pennel K, Quinn J, et al. Relationship between immune checkpoint proteins, tumour microenvironment characteristics, and prognosis in primary operable colorectal cancer. J Pathol Clin Res 2020; 7:121–134. doi: 10.1002/cjp2.193.
doi: 10.1002/cjp2.193
Lee SJ, Jun SY, Lee IH, Kang BW, Park SY, Kim HJ, et al. CD274, LAG3, and IDO1 expressions in tumor-infiltrating immune cells as prognostic biomarker for patients with MSI-high colon cancer. J Cancer Res Clin Oncol 2018; 144:1005–1014. doi: 10.1007/s00432-018-2620-x.
doi: 10.1007/s00432-018-2620-x
Chen J, Chen Z. The effect of immune microenvironment on the progression and prognosis of colorectal cancer. Med Oncol 2014; 31:82doi: 10.1007/s12032-014-0082-9.
doi: 10.1007/s12032-014-0082-9
Saleh R, Taha RZ, Toor SM, Sasidharan Nair V, Murshed K, Khawar M, et al. Expression of immune checkpoints and T cell exhaustion markers in early and advanced stages of colorectal cancer. Cancer Immunol Immunother 2020; 69:1989–1999. doi: 10.1007/s00262-020-02593-w.
doi: 10.1007/s00262-020-02593-w
Burugu S, Gao D, Leung S, Chia SK, Nielsen TO. LAG-3+ tumor infiltrating lymphocytes in breast cancer: clinical correlates and association with PD-1/PD-L1+ tumors. Ann Oncol 2017; 28:2977–2984. doi: 10.1093/annonc/mdx557.
doi: 10.1093/annonc/mdx557
Ascierto PA, Bono P, Bhatia S, Melero I, Nyakas MS, Svane IM, et al. Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with nivolumab in pts with melanoma who progressed during prior anti-PD-1/PD-L1 therapy (mel prior IO) in all-comer and biomarker-enriched populations. Ann Oncol 2017; 28:LBA18doi: 10.1093/annonc/mdx440.011.
doi: 10.1093/annonc/mdx440.011
Ascierto PA, Melero I, Bhatia S, Bono P, Sanborn RE, Lipson EJ, et al. Initial efficacy of anti-lymphocyte activation gene-3 (anti-LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti-PD-1/PD-L1 therapy. J Clin Oncol 2017; 35:9520doi: 10.1200/JCO.2017.35.15_suppl.9520.
doi: 10.1200/JCO.2017.35.15_suppl.9520
Lutzky J, Lutzky J, Feun L, Harbour W. A phase II study of nivolumab + BMS-986016 (relatlimab) in patients with metastatic uveal melanoma (UM) (CA224-094). J Immunother Cancer 2020; 8:A261–A262. doi: 10.1136/jitc-2020-SITC2020.0430.
doi: 10.1136/jitc-2020-SITC2020.0430
Lin C-C, Garralda E, Schoffski P, Hong D, Siu L, Martin M, et al. A phase II, multicenter study of the safety and efficacy of LAG525 in combination with spartalizumab in patients with advanced malignancies. J Immunother Cancer 2020; 8:A235doi: 10.1136/jitc-2020-SITC2020.0387.
doi: 10.1136/jitc-2020-SITC2020.0387
Uboha NV, Milhem MM, Kovacs C, Amin A, Magley A, Das Purkayastha D, et al. Phase II study of spartalizumab (PDR001) and LAG525 in advanced solid tumors and hematologic malignancies. J Clin Oncol 2019; 37:2553doi: 10.1200/JCO.2019.37.15_suppl.2553.
doi: 10.1200/JCO.2019.37.15_suppl.2553
Lipson EJ, Tawbi HA, Schadendorf D, Ascierto PA, Matamala L, Gutiérrez EC, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: Primary phase III results from RELATIVITY-047 (CA224-047). J Clin Oncol 2021; 39:9503doi: 10.1200/JCO.2021.39.15_suppl. 9503.
doi: 10.1200/JCO.2021.39.15_suppl.
Dirix L, Triebel F. AIPAC: a phase IIb study of eftilagimod alpha (IMP321 or LAG-3Ig) added to weekly paclitaxel in patients with metastatic breast cancer. Future Oncol 2019; 15:1963–1973. doi: 10.2217/fon-2018-0807.
doi: 10.2217/fon-2018-0807
Legat A, Maby-El Hajjami H, Baumgaertner P, Cagnon L, Abed Maillard S, Geldhof C, et al. Vaccination with LAG-3Ig (IMP321) and peptides induces specific CD4 and CD8 T-cell responses in metastatic melanoma patients–report of a phase I/IIa clinical trial. Clin Cancer Res 2016; 22:1330–1340. doi: 10.1158/1078-0432.Ccr-15-1212.
doi: 10.1158/1078-0432.Ccr-15-1212
Romano E, Michielin O, Voelter V, Laurent J, Bichat H, Stravodimou A, et al. MART-1 peptide vaccination plus IMP321 (LAG-3Ig fusion protein) in patients receiving autologous PBMCs after lymphodepletion: results of a Phase I trial. J Transl Med 2014; 12:97doi: 10.1186/1479-5876-12-97.
doi: 10.1186/1479-5876-12-97
Felip E, Doger B, Majem M, Carcereny E, Krebs M, Peguero JA, et al. Initial results from a phase II study (TACTI-002) in metastatic non-small cell lung or head and neck carcinoma patients receiving eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab. J Clin Oncol 2020; 38:3100doi: 10.1200/JCO.2020.38.15_suppl.3100.
doi: 10.1200/JCO.2020.38.15_suppl.3100
Atkinson V, Khattak A, Haydon A, Eastgate M, Roy A, Prithviraj P, et al. Eftilagimod alpha, a soluble lymphocyte activation gene-3 (LAG-3) protein plus pembrolizumab in patients with metastatic melanoma. J Immunother Cancer 2020; 8:e001681doi: 10.1136/jitc-2020-001681.
doi: 10.1136/jitc-2020-001681
Jiang H, Ni H, Zhang P, Guo X, Wu M, Shen H, et al. PD-L1/LAG-3 bispecific antibody enhances tumor-specific immunity. Oncoimmunology 2021; 10:1943180doi: 10.1080/2162402x.2021.1943180.
doi: 10.1080/2162402x.2021.1943180
Kraman M, Faroudi M, Allen NL, Kmiecik K, Gliddon D, Seal C, et al. FS118, a bispecific antibody targeting LAG-3 and PD-L1, enhances T-cell activation resulting in potent antitumor activity. Clin Cancer Res 2020; 26:3333–3344. doi: 10.1158/1078-0432.Ccr-19-3548.
doi: 10.1158/1078-0432.Ccr-19-3548