← Back to Search
Emerging Immune Checkpoints For Cancer Therapy
X. Li, W. Hu, X. Zheng, Chu Zhang, Peng Du, Zhuojun Zheng, Y. Yang, J. Wu, M. Ji, Jingting Jiang, Changping Wu
Published 2015 · Medicine
Save to my Library
Download PDFAnalyze on Scholarcy
Background. Immunotherapy with immune checkpoint inhibitors has emerged as promising treatment modality for cancer based on the success of anti-CTLA-4 and -PD-1/PD-L1 antibodies. LAG-3 and TIM-3 are two new immune checkpoints. The aim of this work is to review the role and application of LAG-3 and TIM-3 for cancer immunotherapy. Material and methods. Literatures were searched and collected in Medline/PubMed. Results. LAG-3 is presented as a CD4 homolog type I transmembrane protein which binds MHC class II molecules. LAG-3 negatively regulates T cell proliferation, homeostasis and function. IMP321 is formed of an extracellular portion of human LAG-3 fused to the Fc fraction of human IgG1 and has shown increased T cell responses and tolerability in phase I studies on advanced renal cell cancer. When combined with paclitaxel, IMP321 has exerted immune enhancement and tumor inhibition with no significant IMP321-related adverse events. TIM-3 belongs to the TIM family and mainly negatively regulates Th1 immunity. The TIM-3/galectin-9 pathway contributes to the suppressive tumor microenvironment. TIM-3 overexpression is associated with poor prognosis in a variety of cancers. Both LAG-3 and TIM-3 are coexpressed with other immune checkpoints. The application of LAG-3 or TIM-3 does play an important role in anti-tumor responses, and maybe better when combing with anti-CTLA-4 and anti-PD-1/L1 antibodies. Conclusions. These two immune checkpoints play crucial roles in cancer development and may be used in future clinical practice of cancer therapy.
This paper references
The expression of Tim-3 in peripheral blood of ovarian cancer.
J. Wu (2013)
A Phase I Pharmacokinetic and Biological Correlative Study of IMP321, a Novel MHC Class II Agonist, in Patients with Advanced Renal Cell Carcinoma
C. Brignone (2009)
Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab.
S. Topalian (2014)
Tim-3 on peripheral CD4⁺ and CD8⁺ T cells is involved in the development of glioma.
S. Han (2014)
Allograft rejection is restrained by short-lived TIM-3+PD-1+Foxp3+ Tregs.
S. Gupta (2012)
The CD4‐related molecule, LAG‐3 (CD223), regulates the expansion of activated T cells
C. Workman (2003)
CD3/TCR complex-associated lymphocyte activation gene-3 molecules inhibit CD3/TCR signaling.
S. Hannier (1998)
Targeting regulatory T cells in cancer.
W. L. Byrne (2011)
The negative regulatory function of the lymphocyte‐activation gene‐3 co‐receptor (CD223) on human T cells
L. Maçon-Lemaître (2005)
MHC Class II Engagement by Its Ligand LAG-3 (CD223) Contributes to Melanoma Resistance to Apoptosis
Patrice Hémon (2011)
MHC class ii signal transduction in human dendritic cells induced by a natural ligand, the LAg-3 protein
S Andreae (2003)
CD4/major histocompatibility complex class II interaction analyzed with CD4‐ and lymphocyte activation gene‐3 (LAG‐3)‐Ig fusion proteins
B. Huard (1995)
Ectopic expression of TIM-3 in lung cancers: a potential independent prognostic factor for patients with NSCLC.
Xuewei Zhuang (2012)
A Soluble Lymphocyte Activation Gene-3 Molecule Used as a Vaccine Adjuvant Elicits Greater Humoral and Cellular Immune Responses to Both Particulate and Soluble Antigens1
S. El mir (2000)
Development of lupuslike autoimmune diseases by disruption of the PD1 gene encoding an iTiM motifcarrying immunoreceptor
H nishimura (1999)
Phase I Study of Ipilimumab, an Anti–CTLA-4 Monoclonal Antibody, in Patients with Relapsed and Refractory B-Cell Non–Hodgkin Lymphoma
S. Ansell (2009)
Expression of lymphocyte activation gene 3 (LAG‐3) on B cells is induced by T cells
Malgorzata Kisielow (2005)
Soluble human LAG-3 molecule amplifies the in vitro generation of type 1 tumor-specific immunity.
C. Casati (2006)
Proliferation of activated CD1d‐restricted NKT cells is down‐modulated by lymphocyte activation gene‐3 signaling via cell cycle arrest in S phase
Hyun-Jung Byun (2007)
A phase i study of iMP 321 and gemcitabine as the front - line therapy in patients with advanced pancreatic adenocarcinoma
A Wang-gillam (2013)
Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen–specific CD8+ T cell dysfunction in melanoma patients
J. Fourcade (2010)
intrinsic and extrinsic control of peripheral T - cell tolerance by costimulatory molecules of the CD 28 / B 7 family
H Bour-Jordan (2011)
interactions between PD1 and PD - L 1 promote tolerance by blocking the TCRinduced stop signal
BT Fife (2009)
Immunotherapy for Non-Small Cell Lung Cancer
S. H. Yoon (2014)
Therapeutic gene modified cell based cancer vaccines.
A. Kozłowska (2013)
Tim-3 Expression in Cervical Cancer Promotes Tumor Metastasis
Y. Cao (2013)
Analysis of Tim-3 as a therapeutic target in prostate cancer.
Yongrui Piao (2017)
Anti-programmed cell death protein-1/ligand-1 therapy in different cancers
B. Homet Moreno (2015)
TIM3+FOXP3+ regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer
Kaori Sakuishi (2013)
A soluble LAG-3 protein as an immunopotentiator for therapeutic vaccines: Preclinical evaluation of IMP321.
S. Fougeray (2006)
identification of a human LAG-3 and TIM-3 in cancer therapy
SA Joosten (2007)
Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance
Catherine A. Sabatos (2003)
Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity
Kaori Sakuishi (2010)
Tim-3 and Tim-3 ligand regulates T helper type 1 responses and D ow nl oa de d by [ R ye rs on U ni ve rs ity L
CA Sabatos (2003)
Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens
E. Baixeras (1992)
CTLA‐4 regulates cell cycle progression during a primary immune response
R. Greenwald (2002)
Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease
L. Monney (2002)
Negative Regulation of T Cell Homeostasis by Lymphocyte Activation Gene-3 (CD223)1
C. Workman (2005)
PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice
T. Okazaki (2011)
Too Much of a Good Thing? Tim-3 and TCR Signaling in T Cell Exhaustion
R. Ferris (2014)
TIM-3 Expression Characterizes Regulatory T Cells in Tumor Tissues and Is Associated with Lung Cancer Progression
X. Gao (2012)
LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems.
Joseph F. Grosso (2007)
Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial.
R. Motzer (2015)
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)
Identification of a human CD8+ regulatory T cell subset that mediates suppression through the chemokine CC chemokine ligand 4
S. A. Joosten (2007)
Lymphocyte Activation Gene-3 (CD223) Regulates the Size of the Expanding T Cell Population Following Antigen Activation In Vivo1
C. Workman (2004)
Biochemical Analysis of the Regulatory T Cell Protein Lymphocyte Activation Gene-3 (LAG-3; CD223)1
N. Li (2004)
Role of LAg3 in regulatory T cells
Tim-3+ T-bet+ Tumor-Specific Th1 Cells Colocalize with and Inhibit Development and Growth of Murine Neoplasms1
W. Simmons (2005)
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
S. Topalian (2012)
Decreased Galectin-9 and Increased Tim-3 Expression Are Related to Poor Prognosis in Gastric Cancer
Jing Jiang (2013)
Improved survival with ipilimumab in patients with metastatic melanoma.
F. S. Hodi (2010)
Regulatory T Cells Inhibit Dendritic Cells by Lymphocyte Activation Gene-3 Engagement of MHC Class II1
B. Liang (2008)
The MHC class II ligand lymphocyte activation gene-3 is co-distributed with CD8 and CD3-TCR molecules after their engagement by mAb or peptide-MHC class I complexes.
S. Hannier (1999)
Lymphocyte‐activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes
B. Huard (1994)
Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study.
S. Slovin (2013)
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.
M. Avice (1999)
Ipilimumab in Combination With Paclitaxel and Carboplatin As First-Line Treatment in Stage IIIB/IV Non–Small-Cell Lung Cancer: Results From a Randomized, Double-Blind, Multicenter Phase II Study
A. Tsao (2012)
interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and Downloaded by
C A Sabatos (2003)
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
J. Brahmer (2012)
Role of LAG-3 in regulatory T cells.
C. Huang (2004)
A phase I study of IMP321 and gemcitabine as the front-line therapy in patients with advanced pancreatic adenocarcinoma
A. Wang-Gillam (2012)
Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR–induced stop signal
B. Fife (2009)
Tim-3 Expression Defines Regulatory T Cells in Human Tumors
J. Yan (2013)
Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape.
Seng-Ryong Woo (2012)
The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints.
Nicolas J. Llosa (2015)
TIMs: central regulators of immune responses
D. Hafler (2008)
Intrinsic and extrinsic control of peripheral T‐cell tolerance by costimulatory molecules of the CD28/ B7 family
Hélène Bour-Jordan (2011)
The MHC class ii ligand lymphocyte activation gene3 is codistributed with CD 8 and CD 3TCR molecules after their engagement by mAb or peptideMHC class i complexes
S Hannier (1999)
T cell exhaustion
E. Wherry (2011)
Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs
L. Lu (2013)
Lymphocyte Activation Gene 3 (LAG-3) Modulates the Ability of CD4 T-cells to Be Suppressed In Vivo
Nicholas M. Durham (2014)
Emerging Tim-3 functions in antimicrobial and tumor immunity.
Kaori Sakuishi (2011)
Central regulators of immune responses
D A Hafler (2008)
LAG-3: a regulator of T-cell and DC responses and its use in therapeutic vaccination.
F. Triebel (2003)
The immune cell infiltrate populating meningiomas is composed of mature, antigen-experienced T and B cells.
Liangjuan Fang (2013)
LAG-3 Expression Defines a Subset of CD4+CD25highFoxp3+ Regulatory T Cells That Are Expanded at Tumor Sites
C. Camisaschi (2010)
Restoring Immune Function of Tumor-Specific CD4+ T Cells during Recurrence of Melanoma
S. Goding (2013)
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.
M. Gandhi (2006)
The blockade of immune checkpoints in cancer immunotherapy
D. Pardoll (2012)
Tim-3 on peripheral CD4⁺ and CD8⁺ T cells is involved in the development of glioma.
LAG-3, a novel lymphocyte activation gene closely related to CD4
F. Triebel (1990)
T cell immunoglobulin- and mucin-domain-containing molecule 3 gene polymorphisms and susceptibility to pancreatic cancer
Danian Tong (2012)
Clinical Impact of Checkpoint Inhibitors as Novel Cancer Therapies
K. Shih (2014)
Merkel Polyomavirus-Specific T Cells Fluctuate with Merkel Cell Carcinoma Burden and Express Therapeutically Targetable PD-1 and Tim-3 Exhaustion Markers
O. Afanasiev (2013)
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)
Galectin-9 Increases Tim-3+ Dendritic Cells and CD8+ T Cells and Enhances Antitumor Immunity via Galectin-9-Tim-3 Interactions1
Keiko Nagahara (2008)
Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.
O. Hamid (2013)
Phenotypic Analysis of Prostate-Infiltrating Lymphocytes Reveals TH17 and Treg Skewing
K. Sfanos (2008)
Cutting Edge: Regulatory T Cells from Lung Cancer Patients Directly Inhibit Autologous T Cell Proliferation1
E. Woo (2002)
Tim-3, a negative regulator of anti-tumor immunity.
A. C. Anderson (2012)
Managing immune checkpoint-blocking antibody side effects.
M. Postow (2015)
LAG-3 Regulates Plasmacytoid Dendritic Cell Homeostasis1
C. Workman (2009)
Prospects for TIM3-Targeted Antitumor Immunotherapy.
S. Ngiow (2011)
First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity
C. Brignone (2010)
Nivolumab plus ipilimumab in advanced melanoma.
J. Wolchok (2013)
MHC class II signal transduction in human dendritic cells induced by a natural ligand, the LAG-3 protein (CD223).
S. Andreae (2003)
IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma.
Zhi-Zhang Yang (2012)
Premature Terminal Exhaustion of Friend Virus-Specific Effector CD8+ T Cells by Rapid Induction of Multiple Inhibitory Receptors
S. Takamura (2010)
The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity
C. Zhu (2005)
intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/ B7 family. immunol Rev 2011;241:180–205
H Bour-Jordan (2011)
Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia.
Qing Zhou (2011)
Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma.
A. Ribas (2013)
Cutting Edge: Molecular Analysis of the Negative Regulatory Function of Lymphocyte Activation Gene-31
C. Workman (2002)
Clinical Implications of Phosphorylated STAT3 Expression in De Novo Diffuse Large B-cell Lymphoma
C. Ok (2014)
Tim-3 and Tim-3 ligand regulates T helper type 1 responses and 1712
CA Sabatos (2003)
Promotion of Tissue Inflammation by the Immune Receptor Tim-3 Expressed on Innate Immune Cells
A. Anderson (2007)
CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1.
J. Fourcade (2012)
TIM-3 is expressed in melanoma cells and is upregulated in TGF-beta stimulated mast cells.
Zoltán Wiener (2007)
PD-1 identifies the patient-specific CD8⁺ tumor-reactive repertoire infiltrating human tumors.
A. Gros (2014)
Regulated Compartmentalization of Programmed Cell Death-1 Discriminates CD4+CD25+ Resting Regulatory T Cells from Activated T Cells1
G. Raimondi (2006)
MHC class ii signal transduction in human dendritic cells induced by a natural ligand , the LAg3 protein ( CD 223 )
S Andreae (2003)
Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor.
H. Nishimura (1999)
Restoring function in exhausted CD8 T cells during chronic viral infection
D. Barber (2006)
The MHC class ii ligand lymphocyte activation gene-3 is co-distributed with CD8 and CD3- TCR molecules after their engagement by mAb or peptide- MHC class i complexes. int immunol 1999;11:1745–52
S Hannier (1999)
Functionally Distinct LAG-3 and PD-1 Subsets on Activated and Chronically Stimulated CD8 T Cells1
Joseph F. Grosso (2009)
This paper is referenced by
5th International ACC Symposium: Future and Current Therapeutic Trials in Adrenocortical Carcinoma
A. Hoff (2016)
Uniqueness of Immune-Related Adverse Events in Cancer Patients Treated With Programmed Cell Death Protein 1 / Programmed Death-Ligand 1 Blockade
Ji-qiao Yang (2019)
Immune based therapy for melanoma
Robert Ancuceanu (2016)
Crosstalk between histone modification and DNA methylation orchestrates the epigenetic regulation of the costimulatory factors, Tim-3 and galectin-9, in cervical cancer
L. Zhang (2019)
PD‐1 expression by canine T cells and functional effects of PD‐1 blockade
J. Coy (2017)
A Novel Recombinant Fusion Protein with Soluble PD-1 and TIM-3 Domains Effectively Binds to Cancer Cells
J. Chen (2020)
Combinatorial approach to cancer immunotherapy: strength in numbers
A. Vilgelm (2016)
Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy
Neus Martínez-Bosch (2018)
From Friend to Enemy: Dissecting the Functional Alteration of Immunoregulatory Components during Pancreatic Tumorigenesis
H. Wang (2018)
Rationale for combination of radiation therapy and immune checkpoint blockers to improve cancer treatment
O. Dahl (2019)
Potential value of immunoscoring in rectal cancer patients
Bengt Glimelius (2016)
Tumor immunotherapy: drug-induced neoantigens (xenogenization) and immune checkpoint inhibitors
O. Franzese (2017)
Long-term Survival of Large Cell Neuroendocrine Lung Carcinoma with Bony Metastases: A Case of Immunoprotectivity?
Deborah Paul (2016)
TIM-3 in endometrial carcinomas: an immunotherapeutic target expressed by mismatch repair-deficient and intact cancers
M. Moore (2019)
The Central Role of Inflammation Associated with Checkpoint Inhibitor Treatments
Cristina Vâjâitu (2018)
Notch signaling pathway dampens tumor-infiltrating CD8+ T cells activity in patients with colorectal carcinoma.
W. Yu (2018)
Ferroptosis: a new unexpected chance to treat metastatic melanoma?
Mara Gagliardi (2020)
Clinicopathological analysis of PD-L2 expression in colorectal cancer
P. Guo (2018)
Management of Adverse Events in Cancer Patients Treated With PD-1/PD-L1 Blockade: Focus on Asian Populations
Jiqiao Yang (2019)
The JAK/STAT pathway is involved in the upregulation of PD-L1 expression in pancreatic cancer cell lines.
Toshifumi Doi (2017)
Checkpoint inhibition in myeloma.
D. Benson (2016)
Advances in Immunotherapy for Melanoma: A Comprehensive Review
C. Rodríguez-Cerdeira (2017)
SUV39H1-DNMT3A-mediated epigenetic regulation of Tim-3 and galectin-9 in the cervical cancer
L. Zhang (2020)
Looking past PD-L1: expression of immune checkpoint TIM-3 and its ligand galectin-9 in cervical and vulvar squamous neoplasia
Jacob Curley (2020)
Response to radiotherapy in pancreatic ductal adenocarcinoma is enhanced by inhibition of myeloid-derived suppressor cells using STAT3 anti-sense oligonucleotide
Ayman J Oweida (2020)
Of immune checkpoint maladies and remedies: The throwing of jabs in the oncogenic ring of PDAC.
Olamide T Olaoba (2020)
Immune‐Related Adverse Events From Immune Checkpoint Inhibitors
K. Marrone (2016)
Development and characterization of models of resistance to T-DM1
Juliette Sauveur (2016)
Manipulation of the immune system for cancer defeat: a focus on the T cell inhibitory checkpoint molecules.
P. D'arrigo (2018)
Any progress in pancreatic cancer?
B. Glimelius (2016)
Pancreatic Tumor Microenvironment Modulation by EphB4-ephrinB2 Inhibition and Radiation Combination
Shelby Lennon (2019)
Checkpoints and beyond - Immunotherapy in colorectal cancer.
Tobias Gutting (2019)See more