LAG3 in Cancer Immunotherapy

Monica V. Goldberg and Charles G. Drake

Contents

1 Structural Aspects of LAG-3 270

1.1 Basic Structure 270

1.2 LAG-3 Expression 270

1.3 Binding of Class II MHC 271

1.4 Localization of LAG-3 in T Cells 272

2 LAG-3 Function 272

2.1 Role in CD4 T Cell Function and Expansion 272

2.2 Role of LAG-3 on Regulatory T Cells 273

2.3 Role of LAG-3 on CD8 T Cells 273

2.4 LAG-3 Mechanism of Action 274

3 LAG-3 in Cancer Immunotherapy 275

3.1 Preclinical Studies 275

3.2 Clinical Studies 275

4 Conclusions 276

References 277

Abstract LAG-3 (CD223) is a cell surface molecule expressed on activated T cells (Huard et al. Immunogenetics 39:213-217, 1994), NK cells (Triebel et al. J Exp Med 171:1393-1405, 1990), B cells (Kisielow et al. Eur J Immunol 35:2081-2088, 2005), and plasmacytoid dendritic cells (Workman et al. J Immunol 182:18851891, 2009) that plays an important but incompletely understood role in the function of these lymphocyte subsets. In addition, the interaction between LAG-3 and its major ligand, Class II MHC, is thought to play a role in modulating dendritic

M.V. Goldberg

Johns Hopkins Kimmel Cancer Center, 1650 Orleans Street - CRB 423, Baltimore, MD 21231, USA

Johns Hopkins Kimmel Cancer Center, 1650 Orleans Street - CRB 410, Baltimore, MD 21231, USA

e-mail: [email protected]

G. Dranoff (ed.), Cancer Immunology and Immunotherapy, 269

Current Topics in Microbiology and Immunology 344, DOI 10.1007/82_2010_114 © Springer-Verlag Berlin Heidelberg 2011, published online: 18 November 2010

cell function (Andreae et al. J Immunol 168:3874-3880, 2002). Recent preclinical studies have documented a role for LAG-3 in CD8 T cell exhaustion (Blackburn et al. Nat Immunol 10:29-37, 2009), and blockade of the LAG-3/Class II interaction using a LAG-3 Ig fusion protein is being evaluated in a number of clinical trials in cancer patients. In this review, we will first discuss the basic structural and functional biology of LAG-3, followed by a review of preclinical and clinical data pertinent to a role for LAG-3 in cancer immunotherapy.

Keywords Anergy • CD4 lymphocyte • CD8 lymphocyte • Checkpoint • Tolerance • Treg • Tumor immunology • LAG-3

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