Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Levitsky HI, et al. Role of LAG-3 in regulatory T cells. Immunity. 2004;21:503–13.
Kisielow M, Kisielow J, Capoferri-Sollami G, Karjalainen K. Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells. Eur J Immunol. 2005;35:2081–8.
Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, Hercend T. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med. 1990;171:1393–405.
Workman CJ, Wang Y, El Kasmi KC, Pardoll DM, Murray PJ, Drake CG, Vignali DA. LAG-3 regulates plasmacytoid dendritic cell homeostasis. J Immunol. 2009;182:1885–91.
Huard B, Mastrangeli R, Prigent P, Bruniquel D, Donini S, El-Tayar N, Maigret B, Dreano M, Triebel F. Characterization of the major histocompatibility complex class II binding site on LAG-3 protein. Proc Natl Acad Sci U S A. 1997;94:5744–9.
Wang JH, Meijers R, Xiong Y, Liu JH, Sakihama T, Zhang R, Joachimiak A, Reinherz EL. Crystal structure of the human CD4 N-terminal two-domain fragment complexed to a class II MHC molecule. Proc Natl Acad Sci U S A. 2001;98:10799–804.
Huard B, Prigent P, Tournier M, Bruniquel D, Triebel F. CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur J Immunol. 1995;25:2718–21.
Weber S, Karjalainen K. Mouse CD4 binds MHC class II with extremely low affinity. Int Immunol. 1993;5:695–8.
Li N, Workman CJ, Martin SM, Vignali DA. Biochemical analysis of the regulatory T cell protein lymphocyte activation gene-3 (LAG-3; CD223). J Immunol. 2004;173:6806–12.
Maruhashi T, Okazaki IM, Sugiura D, Takahashi S, Maeda TK, Shimizu K, Okazaki T. LAG-3 inhibits the activation of CD4(+) T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII. Nat Immunol. 2018;19:1415–26.
Workman CJ, Dugger KJ, Vignali DA. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J Immunol. 2002;169:5392–5.
MacLachlan BJ, Mason GH, Greenshields-Watson A, Triebel F, Gallimore A, Cole DK, Godkin A. Molecular characterization of HLA class II binding to the LAG-3 T cell co-inhibitory receptor. Eur J Immunol. 2021;51:331–41.
Baixeras E, Huard B, Miossec C, Jitsukawa S, Martin M, Hercend T, Auffray C, Triebel F, Piatier-Tonneau D. haracterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. J Exp Med. 1992;176:327–37.
Dumic J, Dabelic S, Flogel M. Galectin-3: an open-ended story. Biochim Biophys Acta. 2006;1760:616–35.
Kouo T, Huang L, Pucsek AB, Cao M, Solt S, Armstrong T, Jaffee E. 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;3:412–23.
Liu W, Tang L, Zhang G, Wei H, Cui Y, Guo L, Gou Z, Chen X, Jiang D, Zhu Y, et al. Characterization of a novel C-type lectin-like gene, LSECtin: demonstration of carbohydrate binding and expression in sinusoidal endothelial cells of liver and lymph node. J Biol Chem. 2004;279:18748–58.
Tang L, Yang J, Liu W, Tang X, Chen J, Zhao D, Wang M, Xu F, Lu Y, Liu B, et al. Liver sinusoidal endothelial cell lectin, LSECtin, negatively regulates hepatic T-cell immune response. Gastroenterology. 2009;137(1498–1508):e1491-1495.
Wang J, Sanmamed MF, Datar I, Su TT, Ji L, Sun J, Chen L, Chen Y, Zhu G, Yin W, et al. Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3. Cell. 2019;176(334–347): e312.
Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, Ge P, Umanah GE, Brahmachari S, Shin JH, Kang HC, Zhang J, Xu J, Chen R, Park H, Andrabi SA, Kang SU, Gonçalves RA, Liang Y, Zhang S, Qi C, Lam S, Keiler JA, Tyson J, Kim D, Panicker N, Yun SP, Workman CJ, Vignali DA, Dawson VL, Ko HS, Dawson TM. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science. 2016;353(6307):aah3374. https://doi.org/10.1126/science.aah3374.
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;193:3101–12.
Bruniquel D, Borie N, Hannier S, Triebel F. Regulation of expression of the human lymphocyte activation gene-3 (LAG-3) molecule, a ligand for MHC class II. Immunogenetics. 1998;48:116–24.
Sun H, Sun C, Xiao W. Expression regulation of co-inhibitory molecules on human natural killer cells in response to cytokine stimulations. Cytokine. 2014;65:33–41.
Hannier S, Tournier M, Bismuth G, Triebel F. CD3/TCR complex-associated lymphocyte activation gene-3 molecules inhibit CD3/TCR signaling. J Immunol. 1998;161:4058–65.
Huard B, Tournier M, Hercend T, Triebel F, Faure F. Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes. Eur J Immunol. 1994;24:3216–21.
Workman CJ, Vignali DA. Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223). J Immunol. 2005;174:688–95.
Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, Betts MR, Freeman GJ, Vignali DA, Wherry EJ. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10:29–37.
Chihara N, Madi A, Kondo T, Zhang H, Acharya N, Singer M, Nyman J, Marjanovic ND, Kowalczyk MS, Wang C, et al. Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature. 2018;558:454–9.
Grosso JF, Goldberg MV, Getnet D, Bruno TC, Yen HR, Pyle KJ, Hipkiss E, Vignali DA, Pardoll DM, Drake CG. Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J Immunol. 2009;182:6659–69.
Grosso JF, Kelleher CC, Harris TJ, Maris CH, Hipkiss EL, De Marzo A, Anders R, Netto G, Getnet D, Bruno TC, et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest. 2007;117:3383–92.
Huang RY, Eppolito C, Lele S, Shrikant P, Matsuzaki J, Odunsi K. LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling and dampen antitumor immunity in a murine ovarian cancer model. Oncotarget. 2015;6:27359–77.
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.
Huard B, Tournier M, Triebel F. LAG-3 does not define a specific mode of natural killing in human. Immunol Lett. 1998;61:109–12.
Ohs I, Ducimetiere L, Marinho J, Kulig P, Becher B, Tugues S. Restoration of Natural Killer Cell Antimetastatic Activity by IL12 and Checkpoint Blockade. Cancer Res. 2017;77:7059–71.
Merino A, Zhang B, Dougherty P, Luo X, Wang J, Blazar BR, Miller JS, Cichocki F. Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming. J Clin Invest. 2019;129:3770–85.
Brignone C, Escudier B, Grygar C, Marcu M, Triebel F. A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma. Clin Cancer Res. 2009;15:6225–31.
Brignone C, Grygar C, Marcu M, Schakel K, Triebel F. A soluble form of lymphocyte activation gene-3 (IMP321) induces activation of a large range of human effector cytotoxic cells. J Immunol. 2007;179:4202–11.
Workman CJ, Vignali DA. The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells. Eur J Immunol. 2003;33:970–9.
Iouzalen N, Andreae S, Hannier S, Triebel F. LAP, a lymphocyte activation gene-3 (LAG-3)-associated protein that binds to a repeated EP motif in the intracellular region of LAG-3, may participate in the down-regulation of the CD3/TCR activation pathway. Eur J Immunol. 2001;31:2885–91.
Workman CJ, Rice DS, Dugger KJ, Kurschner C, Vignali DA. Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG-3). Eur J Immunol. 2002;32:2255–63.
Maeda TK, Sugiura D, Okazaki IM, Maruhashi T, Okazaki T. Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation. J Biol Chem. 2019;294:6017–26.
Li N, Wang Y, Forbes K, Vignali KM, Heale BS, Saftig P, Hartmann D, Black RA, Rossi JJ, Blobel CP, et al. Metalloproteases regulate T-cell proliferation and effector function via LAG-3. EMBO J. 2007;26:494–504.
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;162:2748–53.
Gorgulho J, Roderburg C, Beier F, Bokemeyer C, Brummendorf TH, Loosen SH, Luedde T. Soluble lymphocyte activation gene-3 (sLAG3) and CD4/CD8 ratio dynamics as predictive biomarkers in patients undergoing immune checkpoint blockade for solid malignancies. Br J Cancer. 2024;130:1013–22.
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-gamma in peripheral blood. Cancer Biomark. 2018;23:341–51.
Delmastro MM, Styche AJ, Trucco MM, Workman CJ, Vignali DA, Piganelli JD. Modulation of redox balance leaves murine diabetogenic TH1 T cells “LAG-3-ing” behind. Diabetes. 2012;61:1760–8.
Lienhardt C, Azzurri A, Amedei A, Fielding K, Sillah J, Sow OY, Bah B, Benagiano M, Diallo A, Manetti R, et al. Active tuberculosis in Africa is associated with reduced Th1 and increased Th2 activity in vivo. Eur J Immunol. 2002;32:1605–13.
Botticelli A, Zizzari IG, Scagnoli S, Pomati G, Strigari L, Cirillo A, Cerbelli B, Di Filippo A, Napoletano C, ScirocchiF, Rughetti A, Nuti M, Mezi S, Marchetti P. The Role of Soluble LAG3 and Soluble Immune Checkpoints Profile in Advanced Head and Neck Cancer: A Pilot Study. J Pers Med. 2021;11(7):651. https://doi.org/10.3390/jpm11070651.
Guo M, Qi F, Rao Q, Sun J, Du X, Qi Z, Yang B, Xia J. Serum LAG-3 Predicts Outcome and Treatment Response in Hepatocellular Carcinoma Patients With Transarterial Chemoembolization. Front Immunol. 2021;12: 754961.
Shapiro M, Herishanu Y, Katz BZ, Dezorella N, Sun C, Kay S, Polliack A, Avivi I, Wiestner A, Perry C. Lymphocyte activation gene 3: a novel therapeutic target in chronic lymphocytic leukemia. Haematologica. 2017;102:874–82.
Sordo-Bahamonde C, Lorenzo-Herrero S, González-Rodríguez AP, Payer ÁR, González-García E, López-Soto A, Gonzalez S. LAG-3 blockade with relatlimab (BMS-986016) restores anti-leukemic responses in chronic lymphocytic leukemia. Cancers (Basel). 2021;13(9):2112. https://doi.org/10.3390/cancers13092112.
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;235:147–53.
Ueda K, Uemura K, Ito N, Sakai Y, Ohnishi S, Suekane H, Kurose H, Hiroshige T, Chikui K, Nishihara K, et al. Soluble Immune Checkpoint Molecules as Predictors of Efficacy in Immuno-Oncology Combination Therapy in Advanced Renal Cell Carcinoma. Curr Oncol. 2024;31:1701–12.
Chen J, Chen Z. The effect of immune microenvironment on the progression and prognosis of colorectal cancer. Med Oncol. 2014;31:82.
Gandhi MK, Lambley E, Duraiswamy J, Dua U, Smith C, Elliott S, Gill D, Marlton P, Seymour J, Khanna R. Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-cell function in Hodgkin lymphoma patients. Blood. 2006;108:2280–9.
Hemon P, Jean-Louis F, Ramgolam K, Brignone C, Viguier M, Bachelez H, Triebel F, Charron D, Aoudjit F, Al-Daccak R, Michel L. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis. J Immunol. 2011;186:5173–83.
Byun HJ, Jung WW, Lee DS, Kim S, Kim SJ, Park CG, Chung HY, Chun T. Proliferation of activated CD1d-restricted NKT cells is down-modulated by lymphocyte activation gene-3 signaling via cell cycle arrest in S phase. Cell Biol Int. 2007;31:257–62.
Demeure CE, Wolfers J, Martin-Garcia N, Gaulard P, Triebel F. T Lymphocytes infiltrating various tumour types express the MHC class II ligand lymphocyte activation gene-3 (LAG-3): role of LAG-3/MHC class II interactions in cell-cell contacts. Eur J Cancer. 2001;37:1709–18.
Keane C, Law SC, Gould C, Birch S, Sabdia MB, Merida de Long L, Thillaiyampalam G, Abro E, Tobin JW, Tan X, et al. LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia. Cancers (Basel). 2020;4:1367–77.
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(8):2500. https://doi.org/10.3390/jcm9082500.
Okamura T, Fujio K, Shibuya M, Sumitomo S, Shoda H, Sakaguchi S, Yamamoto K. CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2. Proc Natl Acad Sci U S A. 2009;106:13974–9.
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(2075–2082): e2074.
Deng WW, Mao L, Yu GT, Bu LL, Ma SR, Liu B, Gutkind JS, Kulkarni AB, Zhang WF, Sun ZJ. LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma. Oncoimmunology. 2016;5: e1239005.
Ghosh S, Sharma G, Travers J, Kumar S, Choi J, Jun HT, Kehry M, Ramaswamy S, Jenkins D. TSR-033, a Novel Therapeutic Antibody Targeting LAG-3, Enhances T-Cell Function and the Activity of PD-1 Blockade In Vitro and In Vivo. Mol Cancer Ther. 2019;18:632–41.
Guo M, Yuan F, Qi F, Sun J, Rao Q, Zhao Z, Huang P, Fang T, Yang B, Xia J. Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8(+)T cells in hepatocellular carcinoma using multiplex quantitative analysis. J Transl Med. 2020;18:306.
Son Y, Shin NR, Kim SH, Park SC, Lee HJ. Fibrinogen-like protein 1 modulates sorafenib resistance in human hepatocellular carcinoma cells. Int J Mol Sci. 2021;22(10):5330. https://doi.org/10.3390/ijms22105330.
Sun C, Gao W, Liu J, Cheng H, Hao J. FGL1 regulates acquired resistance to Gefitinib by inhibiting apoptosis in non-small cell lung cancer. Respir Res. 2020;21:210.
Zhang Y, Qiao HX, Zhou YT, Hong L, Chen JH. Fibrinogen-like-protein 1 promotes the invasion and metastasis of gastric cancer and is associated with poor prognosis. Mol Med Rep. 2018;18:1465–72.
Xu F, Liu J, Liu D, Liu B, Wang M, Hu Z, Du X, Tang L, He F. LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res. 2014;74:3418–28.
Zuazo M, Arasanz H, Fernandez-Hinojal G, Garcia-Granda MJ, Gato M, Bocanegra A, Martinez M, Hernandez B, Teijeira L, Morilla I, et al. Functional systemic CD4 immunity is required for clinical responses to PD-L1/PD-1 blockade therapy. EMBO Mol Med. 2019;11: e10293.
Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, Eppolito C, Qian F, Lele S, Shrikant P, 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;107:7875–80.
Gestermann N, Saugy D, Martignier C, Tille L, Fuertes Marraco SA, Zettl M, Tirapu I, Speiser DE, Verdeil G. LAG-3 and PD-1+LAG-3 inhibition promote anti-tumor immune responses in human autologous melanoma/T cell co-cultures. Oncoimmunology. 2020;9:1736792.
Wierz M, Pierson S, Guyonnet L, Viry E, Lequeux A, Oudin A, Niclou SP, Ollert M, Berchem G, Janji B, et al. Dual PD1/LAG3 immune checkpoint blockade limits tumor development in a murine model of chronic lymphocytic leukemia. Blood. 2018;131:1617–21.
Zelba H, Bedke J, Hennenlotter J, Mostbock S, Zettl M, Zichner T, Chandran A, Stenzl A, Rammensee HG, Gouttefangeas C. PD-1 and LAG-3 Dominate Checkpoint Receptor-Mediated T-cell Inhibition in Renal Cell Carcinoma. Cancer Immunol Res. 2019;7:1891–9.
Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutierrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, et al. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022;386:24–34.
Hemenway G, Anker JF, Riviere P, Rose BS, Galsky MD, Ghatalia P. Advancements in Urothelial Cancer Care: Optimizing Treatment for Your Patient. Am Soc Clin Oncol Educ Book. 2024;44: e432054.
Feeney K, Joubert WL, Bordoni RE, Babu S, Marimuthu S, Hipkin B, Huang L, Tam R, Rivera MA. RELATIVITY-123: A phase 3, randomized, open-label study of nivolumab (NIVO) + relatlimab (RELA) fixed-dose combination (FDC) versus regorafenib or trifluridine + tipiracil (TAS-102) in later-line metastatic colorectal cancer (mCRC). Journal of Clinical Oncology. 2023;41:TPS278–TPS278.
Amaria RN, Postow M, Burton EM, Tetzlaff MT, Ross MI, Torres-Cabala C, Glitza IC, Duan F, Milton DR, Busam K, et al. Neoadjuvant relatlimab and nivolumab in resectable melanoma. Nature. 2022;611:155–60.
Hegewisch-Becker S, Mendez G, Chao J, Nemecek R, Feeney K, Van Cutsem E, Al-Batran SE, Mansoor W, Maisey N, Pazo Cid R, et al. First-Line Nivolumab and Relatlimab Plus Chemotherapy for Gastric or Gastroesophageal Junction Adenocarcinoma: The Phase II RELATIVITY-060 Study. J Clin Oncol. 2024;42:2080–93.
Andre T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020;383:2207–18.
Overman MJ, Gelsomino F, Aglietta M, Wong M, Limon Miron ML, Leonard G, García-Alfonso P, Hill AG, Cubillo Gracian A, Van Cutsem E, El-Rayes B, McCraith SM, He B, Lei M, Lonardi S. Nivolumab plus relatlimab in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study. J Immunother Cancer. 2024;12(5):e008689. https://doi.org/10.1136/jitc-2023-008689.
Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, Desai J, Hill A, Axelson M, Moss RA, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18:1182–91.
Hamid O, Wang D, Kim TM, Kim S-W, Lakhani NJ, Johnson ML, Groisberg R, Papadopoulos KP, Kaczmar JM, Middleton MR, et al. Clinical activity of fianlimab (REGN3767), a human anti-LAG-3 monoclonal antibody, combined with cemiplimab (anti-PD-1) in patients (pts) with advanced melanoma. J Clin Oncol. 2021;39:9515–9515.
Baramidze A, Gogishvili M, Makharadze T, Zhvania M, Vacharadze K, Crown J, Melkadze T, Hamid O, Long GV, Robert C, Sznol M, Martinez-Said H, Mani J, Chaudhry U, Salvati M, Lowy I, Fury MG, Gullo G. A phase 3 trial of fianlimab (anti–LAG-3) plus cemiplimab (anti–PD-1) versus pembrolizumab in patients with previously untreated unresectable locally advanced or metastatic melanoma. J Clin Oncol. 2023 41:16_suppl,TPS9602-TPS9602. https://doi.org/10.1200/JCO.2023.41.16_suppl.TPS9602.
Andre T, Pietrantonio F, Avallone A, Gumus M, Wyrwicz L, Kim JG, Yalcin S, Kwiatkowski M, Lonardi S, Zolnierek J, et al. KEYSTEP-008: phase II trial of pembrolizumab-based combination in MSI-H/dMMR metastatic colorectal cancer. Future Oncol. 2023;19:2445–52.
Garralda E, Sukari A, Lakhani NJ, Patnaik A, Lou Y, Im SA, Golan T, Geva R, Wermke M, de Miguel M, et al. A first-in-human study of the anti-LAG-3 antibody favezelimab plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer. ESMO Open. 2022;7: 100639.
Gutierrez M, Lam WS, Hellmann MD, Gubens MA, Aggarwal C, Tan DSW, Felip E, Chiu JWY, Lee JS, Yang JC, et al. Biomarker-directed, pembrolizumab-based combination therapy in non-small cell lung cancer: phase 2 KEYNOTE-495/KeyImPaCT trial interim results. Nat Med. 2023;29:1718–27.
Hamid O, Lewis KD, Weise A, McKean M, Papadopoulos KP, Crown J, Kim TM, Lee DH, Thomas SS, Mehnert J, et al. Phase I Study of Fianlimab, a Human Lymphocyte Activation Gene-3 (LAG-3) Monoclonal Antibody, in Combination With Cemiplimab in Advanced Melanoma. J Clin Oncol. 2024;42:2928–38.
Luke JJ, Patel MR, Blumenschein GR, Hamilton E, Chmielowski B, Ulahannan SV, Connolly RM, Santa-Maria CA, Wang J, Bahadur SW, et al. The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial. Nat Med. 2023;29:2814–24.
Ren Z, Guo Y, Bai Y, Ying J, Meng Z, Chen Z, Gu S, Zhang J, Liang J, Hou X, et al. Tebotelimab, a PD-1/LAG-3 bispecific antibody, in patients with advanced hepatocellular carcinoma who had failed prior targeted therapy and/or immunotherapy: An open-label, single-arm, phase 1/2 dose-escalation and expansion study. J Clin Oncol. 2023;41:578–578.
Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, Gandhi L, Redig AJ, Rodig SJ, Asahina H, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. 2016;7:10501.
Johnson DB, Nixon MJ, Wang Y, Wang DY, Castellanos E, Estrada MV, Ericsson-Gonzalez PI, Cote CH, Salgado R, Sanchez V, Dean PT, Opalenik SR, Schreeder DM, Rimm DL, Kim JY, Bordeaux J, Loi S, Horn L, Sanders ME, Ferrell PB Jr, Xu Y, Sosman JA, Davis RS, Balko JM. Tumor-specific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement. JCI Insight. 2018;3(24):e120360. https://doi.org/10.1172/jci.insight.120360.
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: e1249561.
Gide TN, Quek C, Menzies AM, Tasker AT, Shang P, Holst J, Madore J, Lim SY, Velickovic R, Wongchenko M, et al. Distinct Immune Cell Populations Define Response to Anti-PD-1 Monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy. Cancer Cell. 2019;35(238–255): e236.
Yap TA, LoRusso PM, Wong DJ, Hu-Lieskovan S, Papadopoulos KP, Holz JB, Grabowska U, Gradinaru C, Leung KM, Marshall S, et al. A Phase 1 First-in-Human Study of FS118, a Tetravalent Bispecific Antibody Targeting LAG-3 and PD-L1 in Patients with Advanced Cancer and PD-L1 Resistance. Clin Cancer Res. 2023;29:888–98.
Chen BJ, Dashnamoorthy R, Galera P, Makarenko V, Chang H, Ghosh S, Evens AM. The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma. Oncotarget. 2019;10:2030–40.
Chen C, Liang C, Wang S, Chio CL, Zhang Y, Zeng C, Chen S, Wang C, Li Y. Expression patterns of immune checkpoints in acute myeloid leukemia. J Hematol Oncol. 2020;13:28.
Yang ZZ, Kim HJ, Villasboas JC, Chen YP, Price-Troska T, Jalali S, Wilson M, Novak AJ, Ansell SM. Expression of LAG-3 defines exhaustion of intratumoral PD-1(+) T cells and correlates with poor outcome in follicular lymphoma. Oncotarget. 2017;8:61425–39.
Williams P, Basu S, Garcia-Manero G, Hourigan CS, Oetjen KA, Cortes JE, Ravandi F, Jabbour EJ, Al-Hamal Z, Konopleva M, et al. The distribution of T-cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acute myeloid leukemia. Cancer. 2019;125:1470–81.
Timmerman J, Lavie D, Johnson NA, Avigdor A, Borchmann P, Andreadis C, Bazargan A, Gregory G, Keane C, Inna T, et al. Favezelimab (anti–LAG-3) plus pembrolizumab in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after anti–PD-1 treatment: An open-label phase 1/2 study. J Clin Oncol. 2022;40:7545–7545.
Li X, Zhang P, Sun H, Han L, Jiang Z, Yu J. Bispecific antibodies as monotherapy or in combinations for hematological malignancies: latest updates from the EHA 2023 annual meeting. Expert Opin Biol Ther. 2023;23:1193–5.
Chauvin JM, Pagliano O, Fourcade J, Sun Z, Wang H, Sander C, Kirkwood JM, Chen TH, Maurer M, Korman AJ, Zarour HM. TIGIT and PD-1 impair tumor antigen-specific CD8(+) T cells in melanoma patients. J Clin Invest. 2015;125:2046–58.
Mollavelioglu B, Cetin Aktas E, Cabioglu N, Abbasov A, Onder S, Emiroglu S, Tukenmez M, Muslumanoglu M, Igci A, Deniz G, Ozmen V. High co-expression of immune checkpoint receptors PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT on tumor-infiltrating lymphocytes in early-stage breast cancer. World J Surg Oncol. 2022;20:349.
Popp FC, Capino I, Bartels J, Damanakis A, Li J, Datta RR, Löser H, Zhao Y, Quaas A, Lohneis P, Bruns CJ. On behalf Of the pancalyze study group. Expression of immune checkpoint Regulators IDO, VISTA, LAG3, and TIM3 in Resected Pancreatic Ductal Adenocarcinoma. Cancers (Basel). 2021;13(11):2689. https://doi.org/10.3390/cancers13112689.
Sauer N, Janicka N, Szlasa W, Skinderowicz B, Kolodzinska K, Dwernicka W, Oslizlo M, Kulbacka J, Novickij V, Karlowicz-Bodalska K. TIM-3 as a promising target for cancer immunotherapy in a wide range of tumors. Cancer Immunol Immunother. 2023;72:3405–25.
Takamatsu K, Tanaka N, Hakozaki K, Takahashi R, Teranishi Y, Murakami T, Kufukihara R, Niwa N, Mikami S, Shinojima T, et al. Profiling the inhibitory receptors LAG-3, TIM-3, and TIGIT in renal cell carcinoma reveals malignancy. Nat Commun. 2021;12:5547.
Tassi E, Grazia G, Vegetti C, Bersani I, Bertolini G, Molla A, Baldassari P, Andriani F, Roz L, Sozzi G, et al. Early Effector T Lymphocytes Coexpress Multiple Inhibitory Receptors in Primary Non-Small Cell Lung Cancer. Cancer Res. 2017;77:851–61.
Wuerdemann N, Pütz K, Eckel H, Jain R, Wittekindt C, Huebbers CU, Sharma SJ, Langer C, Gattenlöhner S, Büttner R, Speel EJ, Suchan M, Wagner S, Quaas A, Klussmann JP. LAG-3, TIM-3 and VISTA Expression on Tumor-Infiltrating Lymphocytes in Oropharyngeal Squamous Cell Carcinoma-Potential Biomarkers for Targeted Therapy Concepts. Int J Mol Sci. 2020;22(1):379. https://doi.org/10.3390/ijms22010379.
Dai T, Sun H, Liban T, Vicente-Suarez I, Zhang B, Song Y, Jiang Z, Yu J, Sheng J, Lv B. A novel anti-LAG-3/TIGIT bispecific antibody exhibits potent anti-tumor efficacy in mouse models as monotherapy or in combination with PD-1 antibody. Sci Rep. 2024;14:10661.
Cohen EEW, Tourneau CCL, Schaub R, Bartenstein M, Cheng L, Licitra LF. Phase 2 trial of retifanlimab (anti–PD-1) in combination with INCAGN02385 (anti–LAG-3) and INCAGN02390 (anti–TIM-3) as first-line treatment in patients with PD-L1–positive recurrent/metastatic squamous cell carcinoma of the head and neck. Journal of Clinical Oncology. 2023;41:TPS6104–TPS6104.
Hamid O, Gutierrez M, Mehmi I, Dudzisz-Sledz M, Hoyle PE, Wei W, Powderly JD. A phase 1/2 study of retifanlimab (INCMGA00012, Anti–PD-1), INCAGN02385 (Anti–LAG-3), and INCAGN02390 (Anti–TIM-3) combination therapy in patients (Pts) with advanced solid tumors. J Clin Oncol. 2023;41:2599–2599.
Desai J, Meniawy T, Beagle B, Li Z, Mu S, Wu J, Denlinger CS, Messersmith WA. Bgb-A425, an investigational anti-TIM-3 monoclonal antibody, in combination with tislelizumab, an anti-PD-1 monoclonal antibody, in patients with advanced solid tumors: A phase I/II trial in progress. Journal of Clinical Oncology. 2020;38:TPS3146–TPS3146.
Banna GL, Hassan MA, Signori A, Giunta EF, Maniam A, Anpalakhan S, Acharige S, Ghose A, Addeo A. Neoadjuvant Chemo-Immunotherapy for Early-Stage Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2024;7: e246837.
Sordo-Bahamonde C, Lorenzo-Herrero S, Gonzalez-Rodriguez AP, Martínez-Pérez A, Rodrigo JP, García-Pedrero JM, Gonzalez S. Chemo-immunotherapy: a new trend in cancer treatment. Cancers (Basel). 2023;15(11):2912. https://doi.org/10.3390/cancers15112912.
Wang Y, Pattarayan D, Huang H, Zhao Y, Li S, Wang Y, Zhang M, Li S, Yang D. Systematic investigation of chemo-immunotherapy synergism to shift anti-PD-1 resistance in cancer. Res Sq [Preprint]. 2023:rs.3.rs-3290264. https://doi.org/10.21203/rs.3.rs-3290264/v1. Update in: Nat Commun. 2024;15(1):3178. https://doi.org/10.1038/s41467-024-47433-y.
Zhang Y, Zhang K, Wen H, Ge D, Gu J, Zhang C. FGL1 in plasma extracellular vesicles is correlated with clinical stage of lung adenocarcinoma and anti-PD-L1 response. Clin Exp Immunol. 2024;216:68–79.
Qian W, Zhao M, Wang R, Li H. Fibrinogen-like protein 1 (FGL1): the next immune checkpoint target. J Hematol Oncol. 2021;14:147.
Sasikumar PG, Ramachandra M. Small Molecule Agents Targeting PD-1 Checkpoint Pathway for Cancer Immunotherapy: Mechanisms of Action and Other Considerations for Their Advanced Development. Front Immunol. 2022;13: 752065.
Fuchs N, Zhang L, Calvo-Barreiro L, Kuncewicz K, Gabr M. Inhibitors of immune checkpoints: small molecule- and peptide-based approaches. J Pers Med. 2024;14(1):68. https://doi.org/10.3390/jpm14010068.
Abdel-Rahman SA, Rehman AU, Gabr MT. Discovery of First-in-Class Small Molecule Inhibitors of Lymphocyte Activation Gene 3 (LAG-3). ACS Med Chem Lett. 2023;14:629–35.
Add Comment