Immune Inhibitory Molecules LAG-3 and PD-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune Escape

被引：1334

作者：

Woo, Seng-Ryong ^{[1
]}

Turnis, Meghan E. ^{[1
]}

Goldberg, Monica V. ^{[3
,4
,5
]}

Bankoti, Jaishree ^{[1
]}

Selby, Mark ^{[10
]}

Nirschl, Christopher J. ^{[3
,4
,5
]}

Bettini, Matthew L. ^{[1
]}

Gravano, David M. ^{[1
]}

Vogel, Peter

Liu, Chih Long ^{[11
]}

Tangsombatvisit, Stephanie ^{[11
]}

Grosso, Joseph F. ^{[3
,4
,5
]}

Netto, George ^{[7
,8
,9
]}

Smeltzer, Matthew P. ^{[2
]}

Chaux, Alcides ^{[8
]}

Utz, Paul J. ^{[11
]}

Workman, Creg J. ^{[1
]}

Pardoll, Drew M. ^{[6
]}

Korman, Alan J. ^{[10
]}

Drake, Charles G. ^{[3
,4
,5
]}

Vignali, Dario A. A. ^{[1
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA

[2] St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA

[3] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD USA

[4] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Dept Immunol, Baltimore, MD USA

[5] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Dept Urol, Baltimore, MD USA

[6] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Immunol & Hematopoiesis Div, Baltimore, MD USA

[7] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA

[8] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA

[9] Johns Hopkins Univ, Dept Urol, Baltimore, MD USA

[10] Bristol Myers Squibb, Biol Discovery Calif, Milpitas, CA USA

[11] Stanford Univ, Dept Med, Sch Med, Div Rheumatol & Immunol, Stanford, CA 94305 USA

来源：

CANCER RESEARCH | 2012年 / 72卷 / 04期

关键词：

CUTTING EDGE; MICE; TOLERANCE; ACTIVATION; INDUCTION; CANCER; IMMUNOTHERAPY; DEFICIENT; RECEPTORS; THERAPY;

D O I：

10.1158/0008-5472.CAN-11-1620

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. Cancer Res; 72(4); 917-27. (C) 2011 AACR.

引用

页码：917 / 927

页数：11

共 51 条

[51] Induction of postsurgical tumor immunity and T-cell memory by a poorly immunogenic tumor [J].

Zhang, Peisheng ;

Cote, Anik L. ;

de Vries, Victor C. ;

Usherwood, Edward J. ;

Turk, Mary Jo .

CANCER RESEARCH, 2007, 67 (13) :6468-6476

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