Please confirm you are human (Sign Up for free to never see this)
← Back to Search
Immune Inhibitory Molecules LAG-3 And PD-1 Synergistically Regulate T-cell Function To Promote Tumoral Immune Escape.
Seng-Ryong Woo, Meghan E. Turnis, Monica V. Goldberg, Jaishree Bankoti, M. Selby, Christopher J Nirschl, Matthew L Bettini, D. Gravano, P. Vogel, C. Liu, Stephanie Tangsombatvisit, Joseph F. Grosso, G. Netto, M. Smeltzer, Alcides Chaux, P. Utz, C. Workman, D. Pardoll, A. Korman, C. Drake, D. Vignali
Published 2012 · Biology, Medicine
Save to my Library
Download PDFAnalyze on Scholarcy
Inhibitory receptors on immune cells are pivotal regulators of immune escape in cancer. Among these inhibitory receptors, CTLA-4 (targeted clinically by ipilimumab) serves as a dominant off-switch while other receptors such as PD-1 and LAG-3 seem to serve more subtle rheostat functions. However, the extent of synergy and cooperative interactions between inhibitory pathways in cancer remain largely unexplored. Here, we reveal extensive coexpression of PD-1 and LAG-3 on tumor-infiltrating CD4(+) and CD8(+) T cells in three distinct transplantable tumors. Dual anti-LAG-3/anti-PD-1 antibody treatment cured most mice of established tumors that were largely resistant to single antibody treatment. Despite minimal immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in multiple organs, leading to eventual lethality. However, Lag3(-/-)Pdcd1(-/-) mice showed markedly increased survival from and clearance of multiple transplantable tumors. Together, these results define a strong synergy between the PD-1 and LAG-3 inhibitory pathways in tolerance to both self and tumor antigens. In addition, they argue strongly that dual blockade of these molecules represents a promising combinatorial strategy for cancer.
This paper references
Phenotypic analysis of the murine CD4‐related glycoprotein, CD223 (LAG‐3)
C. Workman (2002)
The PD‐1 pathway in tolerance and autoimmunity
Loise M. Francisco (2010)
PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice
T. Okazaki (2011)
The anti-tumor activity of anti-CTLA-4 is mediated through its induction of IFNγ
T. Paradis (2001)
Induction of postsurgical tumor immunity and T-cell memory by a poorly immunogenic tumor.
P. Zhang (2007)
PDL1 regulates the development, maintenance, and function of induced regulatory T cells
LM Francisco (2009)
A newapproach to the adoptive immunotherapyof cancerwith tumor-infiltrating lymphocytes
Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses.
H. Nishimura (1998)
Tumor-infiltratingNY-ESO-1-specificCD8þ T cells are negatively regulatedby LAG-3 andPD-1 in humanovarian cancer
J Matsuzaki (2010)
Regulatory T cells inhibit dendritic cells by lymphocyte activation gene- 3 engagement of MHC class II
B Liang (2008)
Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells.
Cynthia A Chambers (1997)
IL-35-mediated induction of a potent regulatory T cell population
L. Collison (2010)
How regulatory T cells work
D. Vignali (2008)
LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems.
Joseph F. Grosso (2007)
Improving T cell therapy for cancer.
A. Foster (2006)
A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes.
S. Rosenberg (1986)
Cutting Edge: Molecular Analysis of the Negative Regulatory Function of Lymphocyte Activation Gene-31
C. Workman (2002)
PD-L1 regulates the development, maintenance, and function of induced regulatory T cells
Loise M. Francisco (2009)
Cancer Res Cancer Research
The CD4‐related molecule, LAG‐3 (CD223), regulates the expansion of activated T cells
C. Workman (2003)
Costimulatory and coinhibitory receptors in anti‐tumor immunity
Gregory Driessens (2009)
The anti-tumor activity of anti-CTLA-4 is mediated through its induction of IFN gamma.
T. Paradis (2001)
Functionally Distinct LAG-3 and PD-1 Subsets on Activated and Chronically Stimulated CD8 T Cells1
Joseph F. Grosso (2009)
Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice.
H. Nishimura (2001)
Coregulation ofCD8þT cell exhaustion bymultiple inhibitory receptors during chronic viral infection
SD Blackburn (2009)
LAG-3 in Cancer Immunotherapy.
Monica V. Goldberg (2011)
Tumor-infiltrating NY-ESO-1–specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer
J. Matsuzaki (2010)
CD4+ T cell tolerance to parenchymal self-antigens requires presentation by bone marrow-derived antigenpresenting cells
AJ Adler (1998)
Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4
P. Waterhouse (1995)
LAG-3 Regulates Plasmacytoid Dendritic Cell Homeostasis1
C. Workman (2009)
Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection
S. Blackburn (2009)
Tumorinfiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer
J Matsuzaki (2010)
Susceptibility to measles virus-induced encephalitis in mice correlates with impaired antigen presentation to cytotoxic T lymphocytes.
S. Niewiesk (1993)
The multiple antigen blot assay (MABA): a simple immunoenzymatic technique for simultaneous screening of multiple antigens.
O. Noya (1998)
Similar immune response to nonlethal infection with herpes simplex virus-1 in sensitive (BALB/c) and resistant (C57BL/6) strains of mice.
G. Brenner (1994)
Lymphoproliferation in CTLA-4deficient mice is mediated by costimulation-dependent activation of CD4þ T cells
CA Chambers (1997)
RegulatoryTcells inhibit dendritic cells by lymphocyte activation gene3 engagement of MHC class II
B Liang (2008)
CTLA-4 suppresses the pathogenicity of self antigen–specific T cells by cell-intrinsic and cell-extrinsic mechanisms
Wataru Ise (2010)
LW,WorkmanCJ.How regulatory Tcellswork.Nat Rev Immunol 2008;8:523–32
DA Vignali (2008)
Regulatory T Cells
G. Kassiotis (2011)
PD-1 and its ligands in tolerance and immunity.
M. Keir (2008)
B7-H1, in early fate decisions of CD8 T cells
Improved survival with ipilimumab in patients with metastatic melanoma.
F. S. Hodi (2010)
Combination therapy with anti-CTL antigen-4 and anti-4-1BB antibodies enhances cancer immunity and reduces autoimmunity.
E. Kocak (2006)
Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor.
H. Nishimura (1999)
Anti–Programmed Death-1 Synergizes with Granulocyte Macrophage Colony-Stimulating Factor–Secreting Tumor Cell Immunotherapy Providing Therapeutic Benefit to Mice with Established Tumors
B. Li (2009)
Cancer immunoediting: from immunosurveillance to tumor escape
Gavin P Dunn (2002)
Cutting Edge: Accelerated Autoimmune Diabetes in the Absence of LAG-3
M. Bettini (2011)
Concomitant Tumor Immunity to a Poorly Immunogenic Melanoma Is Prevented by Regulatory T Cells
M. Turk (2004)
Role of PD-1 and its ligand, B7-H1, in early fate decisions of CD8 T cells.
Monica V. Goldberg (2007)
Differential subcellular localization of the regulatory T‐cell protein LAG‐3 and the coreceptor CD4
Seng-Ryong Woo (2010)
Enhancement of Antitumor Immunity by CTLA-4 Blockade
D. Leach (1996)
Role of LAG-3 in regulatory T cells.
C. Huang (2004)
regulates plasmacytoid dendritic cell homeostasis
CD4+ T Cell Tolerance to Parenchymal Self-Antigens Requires Presentation by Bone Marrow–derived Antigen-presenting Cells
A. Adler (1998)
The PD-1-PD-L pathway in immunological tolerance.
T. Okazaki (2006)
LAG-3 and PD-1 Synergistically Prevent Antitumor Immunity www
Independent Modes of Natural Killing Distinguished in Mice Lacking Lag3
T. Miyazaki (1996)
Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR–induced stop signal
B. Fife (2009)
CTLA-4 Control over Foxp3+ Regulatory T Cell Function
K. Wing (2008)
PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells.
Yoshiko Iwai (2005)
An essential role for Akt1 in dendritic cell function and tumor immunotherapy
Dongsu Park (2006)
Negative Regulation of T Cell Homeostasis by Lymphocyte Activation Gene-3 (CD223)1
C. Workman (2005)
How regulatory Tcellswork
DA Vignali (2008)
Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates.
J. Brahmer (2010)
Natural innate and adaptive immunity to cancer.
M. D. Vesely (2011)
This paper is referenced by
The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma
B. Chen (2019)
Different Expression Characteristics of LAG3 and PD-1 in Sepsis and Their Synergistic Effect on T Cell Exhaustion: A New Strategy for Immune Checkpoint Blockade
Bailin Niu (2019)
Identification of tonsillar CD4+CD25-LAG3+ T cells as naturally occurring IL-10-producing regulatory T cells in human lymphoid tissue.
S. Sumitomo (2017)
Limitations and opportunities for immune checkpoint inhibitors in pediatric malignancies.
J. Park (2017)
A Chimeric Switch-Receptor Targeting PD1 Augments the Efficacy of Second-Generation CAR T Cells in Advanced Solid Tumors.
X. Liu (2016)
Future perspectives in cancer immunotherapy.
M. Tsiatas (2016)
The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation
Wenwen Xu (2018)
Shp-2 Is Dispensable for E stablishing T Cell Exhaustion and for PD-1 Signaling In Vivo Graphical
Giorgia Rota (2018)
Immune Checkpoint Inhibitors.
J. Haanen (2015)
Molecular profiling of primary uveal melanomas with tumor-infiltrating lymphocytes
P. Triozzi (2019)
Targeting CD73 Enhances the Antitumor Activity of Anti-PD-1 and Anti-CTLA-4 mAbs
B. Allard (2013)
Inhibition of Tryptophan-Dioxygenase Activity Increases the Antitumor Efficacy of Immune Checkpoint Inhibitors
Florence Schramme (2019)
Current Landscape of Immunotherapy in Genitourinary Malignancies.
O. Alhalabi (2020)
Recent advances and future of immunotherapy for glioblastoma
Neha Kamran (2016)
OX40 Agonists and Combination Immunotherapy: Putting the Pedal to the Metal
S. Linch (2015)
Context- and Tissue-Specific Regulation of Immunity and Tolerance by Regulatory T Cells.
A. Ulges (2016)
Nivolumab in melanoma: latest evidence and clinical potential
D. Johnson (2015)
PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: A systematic review and meta-analysis.
S. Gandini (2016)
Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation.
A. Anderson (2016)
Exploiting Synergy: Immune-Based Combinations in the Treatment of Prostate Cancer
M. Burotto (2014)
Oncolytic Viruses and Immune Checkpoint Inhibitors: Preclinical Developments to Clinical Trials
J. K. Hwang (2020)
Targeting immune checkpoints: Building better therapeutic puzzle in pancreatic cancer combination therapy.
Sina Abdkarimi (2020)
Immunomodulation via Chemotherapy and Targeted Therapy: A New Paradigm in Breast Cancer Therapy?
J. Stagg (2012)
New Strategies in Neuroblastoma: Therapeutic Targeting of MYCN and ALK
G. Barone (2013)
Cancer immunotherapy: current status and future directions.
F. Ito (2013)
CXCL11-Armed oncolytic poxvirus elicits potent antitumor immunity and shows enhanced therapeutic efficacy
Z. Liu (2016)
Clinical Implications of Co-Inhibitory Molecule Expression in the Tumor Microenvironment for DC Vaccination: A Game of Stop and Go
A. Vasaturo (2013)
On the role of astrocyte analog circuit in neural frequency adaptation
Mahnaz Ranjbar (2015)
Tim-3 and Tim-4 as the potential targets for antitumor therapy
Lin Cheng (2015)
Investigating and reversing T-cell dysfunction in the Eμ-TCL1 mouse model of chronic lymphocytic leukaemia (CLL)
F. McClanahan (2015)
T cell checkpoint regulators in the heart
Nir Grabie (2019)
Expression of lymphocyte immunoregulatory biomarkers in bone and soft-tissue sarcomas
Amanda R. Dancsok (2019)See more